back to indexUnderstanding & Conquering Depression | Huberman Lab Podcast #34
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Welcome to the Huberman Lab Podcast,
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where we discuss science and science-based tools
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for everyday life.
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I'm Andrew Huberman,
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and I'm a professor of neurobiology and ophthalmology
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at Stanford School of Medicine.
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This month, we're talking all about disorders of the mind,
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things like depression, attention deficit disorders,
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eating disorders, schizophrenia, and bipolar disorder.
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During the course of this month,
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we are going to discuss the psychological
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and biological underpinnings of mood disorders of all kinds.
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You'll learn a lot of science.
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You'll also learn a lot about the various treatments
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that exist and that are in development
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for these various mood disorders.
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We will talk about behavioral tools,
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things like exercise, meditation, breath work,
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but also prescription drugs, supplements,
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and novel compounds that are now being tested
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in various clinical trials.
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Across the month, I think you'll start to realize
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that there are common pathways
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underlying many mood disorders.
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In fact, mood disorders that look quite different
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from one another often depend on the action
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of the same neurochemicals or neural circuits
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in the brain and body.
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That actually should be a point of great relief
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because what it means is that by understanding the biology
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of one mood disorder or understanding how one treatment
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or behavioral intervention can impact a mood disorder,
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we gain insight into other mood disorders as well.
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As always, we will discuss science
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and science-related tools
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that people could implement should they choose.
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Before we dive into today's topic,
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I'd like to discuss a very particular set
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of scientific findings that relate to today's topic
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and that are important for understanding all mood disorders
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and all states of motivation, happiness, and sadness,
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as well as depression.
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Basically, I'm going to paraphrase a brief segment
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of my discussion with Dr. Anna Lemke,
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who I sat down with to discuss addiction
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and the biological basis
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of addiction and addiction treatment.
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A very important aspect of that discussion
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was when Dr. Lemke described the pleasure-pain balance,
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literally the circuits in our brains
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that control our sense of pleasure and pain,
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and ultimately whether or not we remain happy
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in our pursuit of pleasure or not.
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This is an absolutely crucial aspect
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to the way that we function in everyday life,
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and especially under conditions of mood disorders.
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The pathway that she was describing
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is the so-called pleasure system.
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However, what most people don't realize
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is that the pleasure system
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is also directly associated with,
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and in fact is the very same system
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that modulates mental or psychological anguish and pain.
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Essentially, what she described
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is that whenever we pursue something
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that we think will bring us pleasure,
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and that could be anything
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that we think will bring us pleasure,
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from food to video games to sex
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to a particular job or goal, short-term or long-term,
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that we experience release of the neuromodulator dopamine.
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Now, dopamine is associated
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with increased levels of motivation and drive.
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It is not the molecule of reward.
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It is the molecule of craving, motivation, and drive.
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However, as Dr. Lemke pointed out,
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when we are in pursuit of something,
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there is a release of dopamine in our brain.
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That makes us feel motivated,
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and in general, it makes us feel good.
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But very shortly thereafter,
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and beneath our conscious awareness,
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there is a tilt of the pleasure-pain balance in the brain,
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literally a shift in the neural circuits
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that underlie pleasure and pain,
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such that every bit of pleasure or pleasure-seeking
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that causes release of dopamine
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will be balanced out by a little bit of pain.
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And we don't experience this as physical pain,
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at least not at first.
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We experience it as craving for more
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of the thing that brought us pleasure.
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Now, that sounds pretty good.
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and then you get a little bit of pain to balance it out.
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It's subconscious, and you experience it
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as the desire to seek out more pleasure.
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However, it's actually more diabolical than that,
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and we really need to keep an eye on this
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if we are to remain happy,
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if we are to remain in pursuit of our goals.
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The crucial thing to understand is that if we remain
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in constant pursuit of pleasure,
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the pain side of the balance tips
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so that each time we are in pursuit
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of that pleasureful thing, activity or substance,
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we are going to experience,
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we literally achieve less dopamine release
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each subsequent time.
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So we get less pleasure,
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and the amount of craving increases.
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Now, after a certain point or threshold,
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we call that addiction.
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And the way to reset the balance,
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and this is very important,
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the way to reset the balance is actually to enter
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into states in which we are not in pursuit of pleasure,
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to literally enter states in which we are bored,
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maybe even a little bored and anxious,
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and that resets the pleasure-pain balance
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so that we can return to our pursuit of pleasure
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in a way that's healthy and that in an ongoing way
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won't lead to this over-tipping
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or this increase in the amount of pain or addiction.
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So this is very important,
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and if this seemed vague,
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what this means is we should always be cautious
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of any state of mind or body or any pursuit
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that leads to very large increases in dopamine,
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and if it does, we should be very careful
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to not pursue that repeatedly over time.
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During today's episode, I'm going to give an example,
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a real-life example of a discussion that I've been in
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with a young man who's 21 years old
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who's dealing with a disruption
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in this pleasure-pain balance.
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He is essentially depressed,
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and he's depressed because of his ongoing pursuit
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of a particular activity
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that initially led to a lot of dopamine,
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but over time has led to less and less dopamine
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and more and more of this pain side of the balance.
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We could call him addicted to that particular activity.
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Whether or not he's addicted by clinical standards or not
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really isn't important.
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What is important is that he experiences this as depression,
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as low affect as it's called, or anhedonia,
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an inability to experience pleasure
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from that thing or from anything else,
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and he's currently undergoing treatment
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through a rebalancing of this pleasure-pain pathway.
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So while I can't reveal his identity to you,
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that wouldn't be appropriate,
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he did give me permission to reveal the general architecture
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of what he's coping with,
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and I spent some hours with him on the phone this week
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talking to him as well as to the various people
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that he's working with to really understand
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what's going on here,
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because I think it can illustrate the relationship
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between dopamine, pleasure, and pain for sake of addiction,
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but also for understanding how to avoid depressive states,
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how to remove ourselves from depressive states.
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And as you'll see today, as we discussed depression,
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many of the molecules and neural pathways
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and biological mechanisms that we know can be used
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to counter depression,
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feed back onto this pleasure-pain balance.
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Before we begin, I'd like to say that this podcast
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is separate from my teaching and research roles at Stanford.
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It is, however, part of my desire and effort
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to bring zero cost to consumer information about science
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and science-related tools to the general public.
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In keeping with that theme,
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I'd like to thank the sponsors of today's podcast.
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Our first sponsor is Inside Tracker.
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Inside Tracker is a personalized nutrition platform
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that analyzes data from blood and DNA
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to help you better understand your body
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and help you reach your health goals.
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I've long been a believer in getting regular blood work done
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for the simple reason that many of the factors
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that impact our immediate and long-term health
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can only be detected from a quality blood test.
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The problem with most blood tests, however,
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is that you get information back about hormone levels,
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metabolic factors, et cetera,
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but you don't really know what to do with that information.
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Some things might be flagged as too high or too low,
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but really interpreting those data and taking action
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to bring those numbers into the ranges that you want
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And Inside Tracker makes all that very easy.
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into the ranges that are right for you.
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If you'd like to try Inside Tracker,
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you can go to insidetracker.com slash Huberman,
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and if you do that, you'll get 25% off
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any of Inside Tracker's plans.
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Just use the code Huberman at checkout.
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Today's episode is also brought to us by Athletic Greens.
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I've been using Athletic Greens since way back in 2012,
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and so I'm delighted that they're sponsoring the podcast.
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The reason I started taking Athletic Greens
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Today's episode is also brought to us by Belcampo.
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Belcampo is a regenerative farm in Northern California
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that raises organic, grass-fed,
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and finished certified humane meats.
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I don't eat a lot of meat.
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Typically, my diet regime is one
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in which I fast until about noon,
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and then I have a lunch which is fairly low carb,
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so I'll have some piece of meat or chicken or fish
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and some salad typically.
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And then in the evening
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is when I tend to emphasize carbohydrates.
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That helps me be really alert during the day
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the various things in our brain and body
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Today, we're discussing depression.
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In particular, we're going to talk about major depression.
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The phrase major depression is used to distinguish
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one form of depression from the other,
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the other one being bipolar depression.
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Bipolar depression, sometimes called bipolar disorder,
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is really characterized by manic highs,
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so where people aren't sleeping
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and they're talking very fast
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and they're buying things and pursuing resources
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that they can't afford,
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they're starting relationships left and right,
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they're manic, followed by periods of crashes
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of feeling very low, lethargic, and so on.
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Bipolar depression is an absolutely crucial thing
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for us to discuss, and therefore,
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we are going to have an entire separate episode
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related to bipolar depression.
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Today, we're going to talk about major depression,
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also sometimes called unipolar depression,
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just because it doesn't have the highs and lows,
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it's more characterized by the lows.
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We're going to talk about the biology, the psychology,
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and the various treatments,
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behavioral, drugs, supplementation, diet, exercise,
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Before we go forward into the material,
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I just want to emphasize that any discussion
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about mood disorders carries with it
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a particular sensitivity,
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and that sensitivity is one related to self-diagnosis.
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Today's episode, and indeed in the future episodes
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for this month on mood disorders,
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you're going to hear various symptomologies
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that are used to diagnose and characterize these disorders.
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If you recognize some of these symptomologies in yourself
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or in others that you know,
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that's an important thing to take note of.
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However, accurate diagnosis really should be done
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by a qualified healthcare professional.
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So at once I'm saying, keep your eyes and your ears up
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for things that sound familiar to you
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that might be of concern.
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And at the same time, I'm saying,
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don't necessarily leap to conclusions.
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Take those flags of concern if they're there
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and bring them to a qualified healthcare professional,
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and they'll be able to properly diagnose you
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as having a particular mood disorder
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or diagnose somebody as having a particular mood disorder
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or not, and that's an essential step.
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I don't say this to protect us.
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I say this really to protect you.
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Okay, let's have a fact-based discussion about depression.
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And I promise you that where we don't know
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certain things about depression, I will be clear to tell you.
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In fact, we are going to talk about some treatments
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for depression that are looking very promising
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and that right now are actually being used more and more.
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And from my read of the mechanistic literature,
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we're still a bit in the dark as to how these work.
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That's actually a common theme of medicine.
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Many times there are treatments that seem promising
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or that look really terrific,
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and there isn't a lot of understanding about mechanism.
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However, any good discussion about neuroscience
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and in particular about mood disorders
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has to get into mechanism.
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So we're going to do that.
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And in doing that, we're going to frame the discussion
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for the tools of how to keep depression at bay
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and how to deal with it
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if you happen to find yourself depressed
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or if you know somebody else who's depressed.
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What is this thing we call depression?
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Well, as I mentioned before,
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it has two forms, bipolar depression,
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which we're not talking about today,
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and major depression,
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also called unipolar depression, is the other.
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Major depression impacts 5% of the population.
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That is an enormous number.
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That means if you're in a class of 100 people,
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five of them are dealing with major depression
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or have at some point.
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Look around you in any environment
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and you can be sure that a good portion of the people
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that you're surrounded by is impacted by depression
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or will be at some point.
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So this is something we really have to take seriously
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and that we want to understand.
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It is the number four cause of disability.
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A lot of people miss work, miss school,
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and before then likely perform poorly in work or school
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due to major depression.
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Now, there's a very serious challenge
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in having a discussion about depression,
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and it relates directly to the challenges
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in diagnosing depression.
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Earlier, I did an episode with Dr. Carl Deisseroth,
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who is indeed a medical doctor and a PhD,
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he's a psychiatrist,
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and he made a very important point,
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which is that the field of psychiatry and psychology
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are confronted with a challenge,
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which is they're trying to understand what's going on
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within the stuff that's in our brains,
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that's deep to our skulls.
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We don't have access to that without brain imaging
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and electrodes and things like that.
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Someone just comes into the office
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and the dissection tool for depression, so to speak,
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In order to determine if somebody has depression or not,
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we have to use language, how they talk about things,
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also how they carry their body,
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also some general patterns of health.
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So let's talk about depression
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the way that clinicians talk about depression,
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because one of the issues is that we use the word depression
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loosely, a lot of people say, oh, you know,
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I'm so depressed, I didn't get this job or I'm so depressed,
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I just, I don't know, I had a really rough week
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or I'm exhausted, I'm so depressed, or I'm so depressed,
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I thought I was going to go on vacation
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and then they canceled the flight, okay?
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That is not clinical depression,
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that's called being bummed out, being sad or disappointed.
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Now that person might be depressed,
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but clinical depression
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actually has some very specific criteria
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and those criteria are mainly characterized
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by the presence of certain things
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and the absence of a few particular things.
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So let's talk about the things that are present
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in somebody that has major depression.
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First of all, there tends to be a lot of grief,
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there tends to be a lot of sadness, that's no surprise.
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The threshold to cry is often a signature of depression.
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Now that doesn't mean that if you cry easily
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that you're depressed, some people cry more easily
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than others, but if you're somebody
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who typically didn't cry easily
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and suddenly you find yourself crying very easily,
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that could be a sign of depression
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and I want to emphasize could.
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There's also this thing that we call anhedonia,
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a general lack of ability to enjoy things,
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things that typically or previously we enjoyed,
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things like food, things like sex, things like exercise,
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things like social gatherings,
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a kind of lack of enjoyment from those things.
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Sometimes that lack of enjoyment is sad
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and sometimes it's just flat, it's just kind of neutral,
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it doesn't feel good because there's nothing there,
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it's like bland food, it's like these experiences
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are analogous to biting into your favorite article of food
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and it just not tasting very good,
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it just doesn't taste like anything at all
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and that's a common symptom of major depression.
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The other one is guilt.
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Oftentimes people with depression will feel very guilty
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about things they have done in the past
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or they'll just generally feel badly about themselves
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and we're going to talk about this
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because it relates to some of the more serious symptomology
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seen in depression sometimes,
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things like self-harm, mutilation or even suicide.
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But for the time being, we want to frame up anhedonia,
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this lack of ability to achieve or experience pleasure,
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a kind of a flat affect as it's called.
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Sometimes even delusional thinking,
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negative delusional thinking and in particular,
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anti-self confabulation.
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What is anti-self confabulation?
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Well, first of all, confabulation is an incredible aspect
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of our mind and our nervous system.
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You sometimes see other forms of confabulation
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in people who have memory deficits,
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either because they have brain damage
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or they have age-related dementia.
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A good example of this would be
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someone with age-related dementia
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sometimes will find themselves in a location in the house
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and not know how they got there.
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And if you ask them, oh, what are you doing here?
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They will create these elaborate stories.
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Oh, you know, I was thinking about going to shopping today
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and I was going to take the bus and then I was going to do,
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they create these elaborate stories, they confabulate.
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And yet that person hasn't left the house in weeks
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and that person doesn't have a driver's license.
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And so they're really just creating this stuff.
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They're not lying to get out of anything,
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they're confabulating.
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It's as if a brain circuit that writes stories
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just starts generating content.
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In major depression, there's often a state of
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delusional anti-self confabulation
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where the confabulations are not directly
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or completely linked to reality,
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but they are ones that make the self,
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the person describing them,
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seem sick or in some way not well.
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A good example would be somebody
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who experiences a physical injury, perhaps.
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Maybe they break their ankle, maybe it's an athlete
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and they also happen to become depressed.
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And you'll talk to them, you say, how are things going?
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And they'll go, oh, it's okay.
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And I don't know, I feel like I'm getting weaker and weaker
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by the day, I'm just not performing well.
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And then you'll talk to the person that they're working with,
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their kinesiologist or whoever the physical therapist is,
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and they'll say, no, they're actually really improving.
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And I tell them they're improving,
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but somehow they're not seeing that improvement.
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They're not registering that improvement.
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You notice that sometimes it's subtle
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and sometimes it's severe, but they'll start confabulating.
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You'll say, I actually heard you're doing much better.
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You're getting better.
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You're taking multiple trips around the building now
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before you could barely get out of bed.
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And they'll say, yeah, well, basically,
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they changed some things about the parking lot
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that make it easier to move around.
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So it's not really me.
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And these aren't people that are just explaining away
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their accomplishments
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because they're trying to brush off praise.
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They are viewing themselves and they're confabulating
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according to a view that is very self-deprecating
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to the point where it doesn't match up with reality.
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It's not what other people see,
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and it's actually not matched up with reality.
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And that's a symptom of depression
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that I think we don't often think about
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or conceptualize enough.
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So it's not just telling people, oh yeah,
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it's not as good as it seems, everything's bad.
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These people really believe that
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and it becomes disconnected from reality.
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So it's if they're sort of sinking into a pit
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and they're losing touch with the realities of the world,
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including data about themselves,
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their ability to move and get around,
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for example, in the particular instance
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that I used as an example, but there are others as well.
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The other common symptomology of major depression
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is what they call vegetative symptoms, okay?
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So vegetative symptoms are symptoms that occur
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without any thinking, without any doing,
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or without any confabulation.
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These are things that are related to our core physiology.
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The word vegetative, you might know it sounds like vegetable.
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It actually relates to a system in the body
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that nowadays is more commonly called
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the autonomic nervous system.
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The vegetative nervous system
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and the autonomic nervous system,
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historically we're considered sort of one in the same,
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and it relates to things like the stress response
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or to our ability to sleep.
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So vegetative symptoms
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be things like constantly being exhausted.
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The person just feels exhausted.
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It's not because they exercise too much.
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It's not necessarily because of a life event.
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It could be, but they're just worn out.
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They don't have the energy they once had.
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So it's not in their heads.
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It's probably, and now I think we have good data
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to support the fact that there's something off.
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Something is disrupted in the autonomic
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or so-called vegetative nervous system.
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And one of the most common symptoms
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of people with major depression,
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one of the signs of major depression
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is early waking and not being able to fall back asleep
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despite being exhausted.
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So waking up at 3 a.m. or 4 a.m. or 5 a.m.,
link |
just spontaneously and not being able to go back to sleep.
link |
I want to emphasize that that could happen
link |
for other reasons as well,
link |
but it is a common symptom
link |
or warning sign of major depression.
link |
So let's talk more about sleep and depression.
link |
It's well-known that the architecture of sleep
link |
is disrupted in depression.
link |
What's the architecture of sleep?
link |
I've done entire episodes about this,
link |
but very briefly in two sentences,
link |
although they'll probably be run on sentences,
link |
early in the night, you tend to have slow wave sleep
link |
more than REM sleep or rapid eye movement sleep.
link |
As the night goes on,
link |
you tend to have more rapid eye movement sleep.
link |
That architecture of slow wave sleep
link |
preceding rapid eye movement sleep
link |
is radically disrupted in major depression.
link |
In addition, the pattern of activity in the brain
link |
during particular phases of sleep is disrupted.
link |
Now this is during sleep.
link |
So this can't be that people are creating
link |
this situation for themselves.
link |
These are real physiological signs
link |
that something is off in this so-called autonomic
link |
or vegetative nervous system.
link |
And then there are some other things
link |
that relate to the autonomic nervous system,
link |
but that we normally think of as more voluntary in nature.
link |
And these are things like decreased appetite.
link |
So you could imagine that one could have decreased appetite
link |
because of the anhedonia, the lack of pleasure from food.
link |
If you don't enjoy food,
link |
then you might be less motivated to eat it.
link |
As well, because of these disruptions
link |
in the autonomic nervous system,
link |
these vegetative symptoms as they're called,
link |
you could imagine that someone would have decreased appetite
link |
because some of the hormones associated with appetite,
link |
hypocretinorexin and things of that sort,
link |
ghrelin, that those will be disrupted.
link |
And if those names of hypocretinorexin and ghrelin
link |
don't make any sense to you, don't worry about it.
link |
What those are just hormones that impact when we eat,
link |
when we feel hungry and when we crave food more,
link |
as well as when we feel full,
link |
we have enough so-called satiety.
link |
If you want to learn more about those,
link |
we did entire episodes on eating and metabolism.
link |
So you can see that the symptomology of major depression
link |
impacts us at multiple levels.
link |
There's the conscious level of how excited we are generally.
link |
Well, that's reduced.
link |
There's grief, there's guilt, there's crying,
link |
but then there's also these vegetative things.
link |
There's disruptions in sleep,
link |
which of course make everything more challenging
link |
We know that sleep is so vital for resetting.
link |
You're waking up early, you can't get back to sleep.
link |
That's going to adjust your affect,
link |
your emotions in negative ways.
link |
We know this and appetite is off
link |
and there are hormones that get disrupted.
link |
So cortisol levels are increased.
link |
In particular, there's a signature pattern of depression
link |
whereby cortisol, this stress hormone
link |
that normally is released in a healthy way
link |
only in the early part of the day
link |
is shifted to late in the day.
link |
In fact, a 9 p.m. peak in cortisol
link |
is one of the physiological signatures
link |
of depressive like states.
link |
It's not the only one, but it is an important one.
link |
So there are a lot of things going on in major depression.
link |
And by now you're probably thinking,
link |
oh goodness, this is dreadful.
link |
Like there's all this terrible stuff.
link |
And indeed it is terrible.
link |
It is a terrible thing to find oneself
link |
in a mode where things feel sad, you feel guilty,
link |
And oftentimes there's also an association
link |
with the anxiety system.
link |
So just because people are exhausted and lethargic
link |
and they don't enjoy things doesn't necessarily mean
link |
that there's an absence of anxiety.
link |
There can also be a lot of anxiety
link |
about what's going to happen to me.
link |
Am I going to be able to achieve my goals in life?
link |
Will I ever get out of this state?
link |
And so things really start to layer on.
link |
And if this sounds depressing to you,
link |
it is indeed depressing.
link |
This is really the place that many people find themselves.
link |
And it's a pit that they just don't know
link |
how to climb out of.
link |
So let's just take a few minutes
link |
and talk about some of the underlying biology
link |
that creates this cloud
link |
or this constellation of symptomology.
link |
I think that's really important to do
link |
because if we want to understand the various treatments,
link |
how they work and why they work and how to implement them,
link |
we have to understand some of the underlying biology.
link |
So let's spend a few minutes talking about
link |
the biology of depression.
link |
What's known, what's not known.
link |
Because in doing that,
link |
I think you'll get a much clearer picture
link |
about why certain tools work to relieve depression
link |
and why others might not.
link |
So one of the most important early findings
link |
in the search for a biological basis of depression
link |
was this finding that there are drugs
link |
that relieve some of the symptoms of depression.
link |
Those drugs generally fall into three major categories,
link |
but the first set of ones that were discovered
link |
were the so-called tricyclic antidepressants
link |
and the MAO inhibitors, the monoamine oxidase inhibitors.
link |
You don't need to understand that nomenclature,
link |
but I'm going to give you a little bit of detail
link |
so that if you want to understand it, you can.
link |
Most of this work took place in the late 1950s
link |
and in the 1960s and continued well until the 1980s
link |
when new classes of drugs were discovered.
link |
And these tricyclic antidepressants
link |
and the MAO inhibitors largely worked
link |
by increasing levels of norepinephrine in the brain,
link |
as well as in the body in some cases.
link |
And they were discovered
link |
through a kind of odd set of circumstances.
link |
We don't have time to go into all the history,
link |
but suffice to say that they were discovered
link |
because of the exploration for drugs
link |
that alter blood pressure.
link |
Norepinephrine impacts blood pressure
link |
and drugs that lower blood pressure,
link |
reduce levels of norepinephrine,
link |
and that in many cases was shown to lead to depression
link |
or depressive-like symptoms.
link |
And so these drugs, these tricyclic drugs
link |
and the MAO inhibitors actually increase norepinephrine.
link |
And frankly, they do quite a good job of relieving some,
link |
if not all of the symptoms of major depression.
link |
However, they carry with them many side effects.
link |
Some of those side effects are side effects related
link |
to blood pressure itself.
link |
By increasing noradrenaline, norepinephrine as it's called,
link |
you raise blood pressure.
link |
That can be dangerous.
link |
That can be uncomfortable.
link |
But they also have a lot of other side effects.
link |
The reason they have other side effects
link |
is because they impact systems in the brain
link |
and in the body that impact things like libido, appetite,
link |
digestion, and others.
link |
And we'll talk about each of those in sequence.
link |
Okay, so the experience that clinicians had
link |
of observing some relief for depression
link |
with the tricyclic antidepressants
link |
and with MAO inhibitors was terrific,
link |
but there were all these side effects,
link |
side effects that people really did not like.
link |
They didn't like these drugs at all.
link |
A lot of people would get dry mouth.
link |
I mentioned the low libido.
link |
They'd have sleep issues, appetite issues, weight gain.
link |
They made some people so uncomfortable
link |
that they preferred not to take them,
link |
even though when they didn't take them,
link |
they had a worsening or a maintenance
link |
of their depressive symptoms.
link |
A decade or so later, there was the discovery
link |
of the so-called pleasure pathways in the brain.
link |
These are pathways, literally groups of neurons
link |
that reside in different locations in the brain,
link |
but connect to one another, so it's a circuit.
link |
And when you stimulate these neurons
link |
with certain behaviors or with electrical stimulation
link |
in an experiment, believe it or not,
link |
that's been done in both animals and humans,
link |
animals and humans become very, very motivated
link |
to get more stimulation of these pathways.
link |
So this pleasure pathway or these circuits for pleasure
link |
are very what we call reinforcing.
link |
In fact, animals and humans will work hard
link |
to get stimulation of these brain areas
link |
even more than they will work to obtain sex, drugs,
link |
or even if they are addicted to a particular drug
link |
and they are in a state of withdrawal,
link |
the ultimate state of craving,
link |
if given a choice, a person or an animal
link |
will select to have stimulation of this pleasure pathway
link |
instead of the drug itself.
link |
And that is a major and significant finding.
link |
This pleasure pathway, as it's sometimes called,
link |
involves areas like the nucleus accumbens
link |
and the ventral tegmental area.
link |
These are areas of the brain that are rich with neurons
link |
that make dopamine.
link |
And if you think to the symptoms of depression,
link |
of anhedonia, a lack of pleasure,
link |
a lack of ability to experience pleasure,
link |
well, that was a smoking gun that there's something wrong
link |
with the dopamine pathway in depression.
link |
And indeed that's the case.
link |
So it's not just norepinephrine,
link |
it's also the dopamine or pleasure pathway
link |
is somehow disrupted.
link |
And then in the 1980s,
link |
there was the discovery of the so-called SSRIs.
link |
Most people are now familiar with the SSRIs,
link |
the selective serotonin reuptake inhibitors.
link |
The SSRIs worked by distinct mechanisms
link |
from the tricyclic antidepressants and the MAO inhibitors.
link |
As their name suggests, SSRI,
link |
selective serotonin reuptake inhibitors,
link |
prevent serotonin from being wiped up from the synapse
link |
after two neurons talk to one another.
link |
What do I mean by that?
link |
Well, here's some very basic neurobiology 101.
link |
If you don't know any neurobiology,
link |
you're going to know some in about 15 seconds.
link |
Neurons communicate with one another
link |
by spitting out chemicals into the little gap between them.
link |
The little gap between them is called the synapse
link |
or by the Brits, the synapse.
link |
Those chemicals bind to the neuron on the opposite side
link |
and cause changes in the electrical activity
link |
of that neuron on the other side of the synapse.
link |
Serotonin is one such neurotransmitter
link |
or more specifically, it's a neuromodulator.
link |
It can change the activity of large groups of neurons
link |
in very meaningful ways.
link |
Selective serotonin reuptake inhibitor means
link |
when a person takes this drug,
link |
some of those drugs include things like Prozac or Zoloft,
link |
the more typical names or more generic names
link |
are things like fluoxetine.
link |
When people take those,
link |
more serotonin hangs out in the synapse
link |
and is able to be taken up by the neuron
link |
on the opposite side
link |
because of this selective reuptake inhibition.
link |
It prevents the clearance of serotonin from the synapse
link |
and thereby more serotonin can have an effect.
link |
So SSRIs don't increase the total amount of serotonin
link |
They change how effective the serotonin
link |
that's already in the brain is
link |
at changing the activity of neurons, okay?
link |
So they don't increase serotonin,
link |
they increase the efficacy or the function of serotonin
link |
in the way that I just described.
link |
So that was more than 15 seconds,
link |
but now you understand how SSRIs work.
link |
And I wouldn't be talking about SSRIs
link |
if they didn't in fact work.
link |
Yes, there are many problems with SSRIs.
link |
They do carry certain side effects in many individuals.
link |
Also about a third of people that take SSRIs
link |
don't derive any benefit.
link |
It doesn't relieve their symptoms of depression.
link |
However, for the other two thirds,
link |
there's often a relief of some,
link |
if not all of the symptoms of major depression.
link |
The problem is the side effects that accompany those SSRIs.
link |
And so these days, SSRIs are a complicated topic.
link |
It's sort of what I would call a barbed wire topic
link |
because we often hear about all the problems with them,
link |
but these drugs also have saved a lot of lives.
link |
They've also improved a lot of lives.
link |
The issue is that they tend to have varying effects
link |
on different individuals
link |
and sometimes varying effects over time.
link |
So they'll work for a while,
link |
then they won't work for a while.
link |
There are also a lot of mysteries about the SSRIs
link |
and those mysteries bother people.
link |
What mysteries am I referring to?
link |
Well, SSRIs increase the amount of serotonin
link |
or more specifically,
link |
they increase the efficacy of serotonin at the synapse.
link |
That happens immediately
link |
or very soon after people start taking SSRIs,
link |
but people generally don't start experiencing any relief
link |
from their symptoms of depression
link |
if they're going to experience them at all
link |
until about two weeks after they start taking these drugs.
link |
So there's something going on there that's not clear.
link |
One idea is that the SSRIs
link |
actually can improve symptoms of depression
link |
or even remove symptoms of depression
link |
through so-called neuroplasticity
link |
by changing the way that neural circuits function.
link |
And there are many studies on this,
link |
but the main categories of studies on SSRIs
link |
that relate to neuroplasticity fall into two camps.
link |
One is the ways in which SSRIs might,
link |
and I want to emphasize might,
link |
be able to trigger the production of more neurons
link |
in the brain, in particular areas of the hippocampus
link |
called the dentate gyrus and others that impact memory.
link |
This is important and we're going to come back to memory.
link |
The other is that the SSRIs have been shown
link |
in various scientific studies
link |
to reopen critical periods of plasticity.
link |
I'll just briefly describe one of those studies.
link |
It was a study done by Lumberto Maffei's group in Pisa
link |
that explored brain plasticity
link |
that's known to be present in young animals
link |
and disappear in older animals.
link |
And this is also true in humans.
link |
Younger humans have a far more plastic brain.
link |
It can change in many more ways,
link |
more easily than can the older brain.
link |
And what they showed was that fluoxetine, Prozac,
link |
given to adult animals,
link |
can reopen this incredible period of plasticity.
link |
It can allow more plasticity to occur.
link |
That was interesting.
link |
I mean, it's purely through increases
link |
in serotonin transmission.
link |
And there are other studies showing that fluoxetine
link |
can increase the number of new neurons
link |
that are born into the adult brain,
link |
so-called neurogenesis, the production of new neurons.
link |
So it's very clear that there are at least
link |
three major chemical systems in the brain,
link |
norepinephrine, dopamine, and serotonin
link |
that relate to and can adjust the symptoms of depression.
link |
And those actually can be divided into separate categories.
link |
So for instance, epinephrine or norepinephrine
link |
is thought to relate to the so-called psychomotor defects,
link |
sometimes called psychomotor retardation.
link |
This is the lethargy.
link |
This is the exhaustion.
link |
This is the inability to get out of bed in the morning.
link |
Dopamine is thought to relate to the anhedonia,
link |
or I should say lack of dopamine in depressive patients
link |
is thought to lead to the anhedonia,
link |
the lack of ability to experience pleasure.
link |
And serotonin is thought to relate to the grief, the guilt,
link |
some of the more cognitive
link |
or more emotional aspects of depression.
link |
So we've got the norepinephrine system
link |
related to activity and alertness,
link |
the dopamine system relating to motivation, pleasure,
link |
and the ability to seek and experience pleasure,
link |
and then the serotonin system that's related to grief.
link |
And unfortunately, brains and organisms don't work
link |
in a simple mathematical way where you just say,
link |
oh, well, this person's experiencing a lot of grief,
link |
but they don't have any problems with lethargy,
link |
and so let's just boost up their serotonin.
link |
On paper, it works,
link |
but oftentimes it doesn't work clinically.
link |
And in another patient,
link |
you might get somebody who can't experience pleasure,
link |
but they're kind of anxious.
link |
They don't have any trouble sleeping,
link |
but they're just much more anxious
link |
and frustrated than they normally are,
link |
and they meet the symptoms of depression.
link |
Well, you might think, oh, well,
link |
do you just give that person some drug to increase dopamine
link |
and everything will be better?
link |
And indeed, in some cases, that's true.
link |
There are drugs like wellbutrin,
link |
which function more specifically on the dopamine system
link |
to increase dopamine,
link |
and they also increase norepinephrine.
link |
Many people get great relief from things like wellbutrin.
link |
They don't really impact the serotonin system so much,
link |
and therefore you don't get a lot of the serotonergic
link |
or serotonin-related side effects.
link |
However, some people feel far too anxious on those drugs.
link |
Some people get addicted to those drugs in a way,
link |
because a lot of those drugs that increase dopamine
link |
make you want more of those drugs.
link |
So you start to realize that what makes sense on paper
link |
doesn't always make sense clinically,
link |
and this is why it's complicated,
link |
and a really good psychologist
link |
and a really good psychiatrist will work with someone
link |
to try and pull and push on these various systems
link |
to find the combination of drugs
link |
that may be or may not be correct for them.
link |
There's a fourth aspect of the chemistry of depression
link |
that's really important to understand, and that's pain.
link |
We've talked about pain on this podcast before,
link |
but even if you didn't hear the episode
link |
on pleasure and pain,
link |
just want to emphasize that pain is something
link |
that we experience in our body,
link |
no surprise there, an injury, a cut, et cetera,
link |
but that we also experience emotional pain,
link |
and those systems are linked in very intricate ways.
link |
There's actually some data showing that pain relievers,
link |
Tylenol, aspirin, these sorts of things
link |
can help certain people with emotional pain.
link |
Now, I'm not recommending people run out
link |
and take those things for emotional pain,
link |
but actually, if you think about that,
link |
it shouldn't come as any surprise
link |
given the enormous number of people that take painkillers,
link |
opioids, and things like them
link |
to try and relieve their psychological pain,
link |
and as we know, those drugs are very, very problematic
link |
for many individuals.
link |
They can help certain individuals,
link |
but they are very prone to abuse,
link |
and they can induce addiction very easily
link |
in a number of people.
link |
There's a substance that's literally called substance P,
link |
the letter P, that's manufactured by neurons
link |
in our brain and body, which underlies
link |
our sensation of pain, and indeed,
link |
substance P inhibitors have been used to treat depression,
link |
and in some cases, works.
link |
A lot of people with depression are hypersensitive to pain,
link |
and of course, they could have multiple things going on.
link |
They could have chronic pain or chronic injury
link |
and major depression.
link |
So you start to get the constellation
link |
of the many things that could happen.
link |
So that's all I want to say today
link |
about the chemistry underlying depression
link |
or major depression.
link |
There's a lot more there,
link |
but I think if you understand the norepinephrine system
link |
and that it relates to some of these things like lethargy,
link |
the psychomotor defects, as they're called,
link |
dopamine and how it relates to motivation
link |
and lack of motivation and lack of dopamine and depression,
link |
and serotonin and its relationship to grief,
link |
and that low serotonin can lead to extreme grief and shame,
link |
and higher serotonin levels can sometimes restore
link |
a sense of wellbeing and safety
link |
and feeling good about oneself.
link |
If you understand that and you understand that physical pain
link |
is somehow involved in certain cases,
link |
I think you will know more about depression
link |
and its underlying chemistry than most all people out there.
link |
And if you'd like to learn more,
link |
I invite you to pursue searching those terms
link |
further on the internet,
link |
and we'll certainly go into them in more depth,
link |
but that really sets the stage for where we're headed next.
link |
So next, I'd like to talk about hormones
link |
and how they relate to depression.
link |
And I'd also like to talk about stress
link |
and how it relates to depression,
link |
as well as talk about some of the genetics
link |
or the predispositions to depression.
link |
And for those of you that are thinking,
link |
hey, I want the tools, I want to know how to fix depression.
link |
I understand the desire for that.
link |
I will just ask if you hang in here with me
link |
a little bit longer, not only will you learn a lot more
link |
about how this complicated mood disorder works,
link |
some of the more interesting things about it,
link |
but it will also position you to get a lot more
link |
out of the tools that we will describe.
link |
You always have the option to skip forward, of course,
link |
but I think it's important to understand
link |
some of the hormonal and stress-related
link |
aspects of depression.
link |
So let's talk about hormones.
link |
20% of people that have major depression
link |
have low thyroid hormone.
link |
Thyroid hormone is related to metabolism.
link |
Oftentimes we think about thyroid
link |
as only related to having a fast metabolism,
link |
but thyroid is related to all forms of metabolism,
link |
including our ability to synthesize new tissues
link |
like protein and repair injuries.
link |
I did a whole episode on thyroid and growth hormone.
link |
If you want to check that out,
link |
all of that is archived at Hubermanlab.com.
link |
It's all timestamped, et cetera.
link |
You can find on YouTube, Apple, Spotify, all those places.
link |
So if you're curious about thyroid hormone
link |
and growth hormone,
link |
and you want to do the deep dive on those,
link |
and you want to learn how to alter their levels
link |
using various approaches, check that out.
link |
But 20% of people with major depression are hypothyroidal.
link |
They don't make enough thyroid.
link |
And that leads to low energy,
link |
low metabolism in the brain and body.
link |
And there's a condition called Hashimoto's,
link |
which is essentially low thyroid output.
link |
And again, I don't want to get into
link |
all the tools related to thyroid.
link |
Sometimes a psychiatrist will prescribe thyroid medication
link |
to increase thyroid output in people that are depressed,
link |
and that will work to relieve the symptoms.
link |
So there isn't necessarily a direct problem
link |
with serotonin, dopamine, and norepinephrine
link |
Sometimes it's a thyroid problem.
link |
So there are certain situations or conditions
link |
that can impact the thyroid hormone system
link |
and make people more susceptible to depression
link |
or make a preexisting depression worse.
link |
And those are things like childbirth.
link |
So it's well known that women who give birth
link |
can often undergo what's called postpartum depression.
link |
It actually comes from the word postpartuition depression.
link |
They give birth, what's happier, what's more joyful
link |
than the birth of a new healthy child,
link |
and they will lapse into a depression.
link |
And that's thought to be hormonally related.
link |
Either directly to the thyroid system
link |
or perhaps to the cortisol system as well.
link |
We'll talk about cortisol in a moment.
link |
As well, certain women during certain phases
link |
of their menstrual cycle experience symptoms
link |
that are very much like clinical depression
link |
and oftentimes are diagnosed
link |
with clinical depression appropriately.
link |
And of course the menstrual cycle is associated
link |
with shifts in hormone levels.
link |
As well, menopause and postmenopausal women
link |
are more susceptible to major depression
link |
regardless of whether or not they've had
link |
that major depression earlier in their life.
link |
So these are things to be on the lookout for
link |
and to definitely talk to a doctor and get a blood panel
link |
that hopefully includes measures of thyroid hormone
link |
and cortisol hormone.
link |
Why cortisol hormone?
link |
Well, more stress is correlated with more bouts
link |
of major depression across the lifespan.
link |
Well, it turns out that as you go
link |
from having one to two to three,
link |
well, when you hit four to five bouts
link |
of really intense to stressful episodes in life,
link |
these tend to be long-term stressful episodes,
link |
your risk for major depression goes way up.
link |
So whether or not you have a genetic predisposition
link |
to depression or not,
link |
one of the best things you can do
link |
to try and avoid getting depressed
link |
is to learn to control your stress system,
link |
to not go from short-term stress,
link |
which everybody experiences,
link |
we all have short-term stressors,
link |
to medium-term stress to long-term stress
link |
and to not have too many bouts of long-term stress
link |
because that probability of getting depressed
link |
And this is something I've seen over and over again,
link |
not just in my scientific career,
link |
but just throughout life,
link |
people in all sorts of domains, young and old,
link |
I've seen that people will go
link |
through a very intense relationship, a breakup.
link |
Sometimes it's the staying together that's stressful.
link |
Sometimes it's a graduate school that can be stressful.
link |
Sometimes it's some other event.
link |
And then some months later, they become depressed.
link |
And that's because the stress system is associated
link |
with the release of cortisol.
link |
The cortisol system can dramatically impact
link |
the way that these different neuromodulators,
link |
dopamine, norepinephrine, and serotonin function.
link |
And so there's this kind of latent
link |
or longer lasting impact on the systems
link |
that impact mood and wellbeing.
link |
So learning how to control your stress is really key.
link |
If you're not depressed or you're somebody
link |
that has not lapsed into a depression recently,
link |
take control of your stress system.
link |
And we did an entire episode on how to conquer stress.
link |
And that involves dealing with stress in the short-term,
link |
the medium-term, and in the long-term.
link |
And there are a lot of different ways to do that.
link |
One of the more important reasons
link |
for learning how to counter stress
link |
in order to offset depression
link |
is that there is a genetic predisposition
link |
that certain people carry to become depressed.
link |
There are these studies now
link |
of many, many thousands of individuals.
link |
These were mainly done in New Zealand,
link |
but these studies have now been done elsewhere,
link |
looking at many tens of thousands of individuals
link |
who carry particular copies of genes,
link |
what they call polymorphisms,
link |
in particular of a gene called 5-HTTLPR,
link |
which is a serotonin transporter.
link |
So this is a gene that controls or regulates
link |
how much serotonin is available in the brain.
link |
If you have this gene, this polymorphism,
link |
it doesn't necessarily mean that you will be depressed,
link |
but it greatly shifts your susceptibility
link |
to depression under conditions of stress.
link |
So I realize some people are listening to this
link |
and some people are watching it on YouTube,
link |
so I'm going to describe this in a way
link |
that doesn't require looking at any graphs.
link |
What I want you to imagine is a very shallow hill,
link |
like a very mellow hill.
link |
It's just a ramp set at about 10 or 15 degrees, okay?
link |
What we're plotting there in your mind
link |
is that with each bout of serious stress,
link |
so that could be trying to finish a degree
link |
or a relationship breakup or a family member that's sick
link |
or the loss of a loved one or a pet,
link |
with each bout of stress,
link |
the probability that you will experience
link |
a major depression goes up.
link |
However, if you carry this gene, this HTTLPR gene,
link |
the steepness of that curve goes way, way up,
link |
or it's actually more like a line,
link |
such that you need far fewer bouts of stress
link |
in order to lapse into a major depression, okay?
link |
So if the typical person who doesn't carry this polymorphism
link |
has to experience two or three or four or five bouts
link |
of stress before they lapse into a depression,
link |
somebody with this gene is susceptible to getting depression
link |
after just one bout or two bouts of intense stress, okay?
link |
So that's how these genes work.
link |
They don't preordain or determine you to be depressed.
link |
They raise a susceptibility, and many in genes,
link |
many things related to heritability in general
link |
And we know there's a strong genetic component to depression.
link |
Well, in what are called concordant monozygotic twins.
link |
So these would be identical twins,
link |
and they can either be in one biological sac
link |
or two biological sacs while in utero,
link |
what's called a monochorionic or dichorionic.
link |
Well, typically it's monochorionic,
link |
and identical twins for which one of those twins
link |
goes on to have major depression,
link |
there's a 50% probability that the other one
link |
will have major depression.
link |
It's not 100% inherited.
link |
It's not 100% genetic, as you might say,
link |
but there's a much higher predisposition for depression.
link |
Whereas in fraternal twins, that number drops,
link |
and in siblings, that number drops to about 25%,
link |
and in half siblings, it's about 10%.
link |
The numbers vary from study to study,
link |
but basically the more closely related you are
link |
to somebody who has major depression,
link |
the more likely it is
link |
that you will also get major depression,
link |
and therefore, if you haven't gotten major depression,
link |
the more likely it is that you should take steps
link |
to learn to mitigate stress,
link |
because stress is the major factor
link |
that can trigger one of these depressive episodes.
link |
Okay, so we've covered a lot related to the stress
link |
and the hormones and the neurochemistry of depression.
link |
In fact, I think this is probably the deepest
link |
I've ever gone into the biology of any topic
link |
on this podcast before getting to any specific tools.
link |
I mentioned that learning how to mitigate stress
link |
and deal with stress, learning how to measure
link |
and adjust your thyroid hormone, those might be useful,
link |
but next I'd like to turn to some very specific tools
link |
that people who both have depression
link |
or who are prone to depression,
link |
as well as people who don't have depression
link |
and simply want to maintain a good mood,
link |
who want to maintain a positive affect
link |
and pursuit of things in life,
link |
what are the things that you can do?
link |
Turns out there are things that you can do
link |
and all of the biology that underlies
link |
the utility of those things,
link |
meaning the reasons those things work
link |
will now make sense to you
link |
because they adjust things like serotonin and dopamine
link |
and they adjust them through very specific pathways.
link |
I know for many people,
link |
learning about mechanism is kind of grueling.
link |
I realize this podcast isn't necessarily one
link |
that you can listen to passively while doing other things,
link |
although I would hope that you could do that
link |
and still enjoy it and extract the information.
link |
Mechanism is so key because mechanism
link |
is a little bit like understanding
link |
some of the chemistry of cooking.
link |
If you read a recipe and you can follow a recipe,
link |
you often hear people say, oh, I can follow a recipe.
link |
That means that if you have every ingredient in that recipe,
link |
you're good, you likely can make that dish,
link |
you can make that meal.
link |
However, if you understand a little bit of the chemistry
link |
of why salt has to be added third and not first,
link |
or why the heat has to be adjusted at a particular time,
link |
well, then not only can you follow a recipe,
link |
but that also gives you flexibility
link |
for when salt isn't available,
link |
or when you want to adjust the flavor of the dish,
link |
or when you want to try a new dish
link |
or you want to get experimental.
link |
So when you understand mechanism,
link |
it puts you in a tremendous place of power
link |
to work with your system.
link |
So it's not just plug and chug,
link |
like take 12 milligrams of this,
link |
you either feel better or you don't,
link |
you can really start to understand how prescription drugs,
link |
supplements, nutrition, behavioral tools,
link |
how those things weave together to either work for you
link |
or not work for you and get you to paths
link |
of healthy mind and body.
link |
So let's think about why any tool would work
link |
to relieve depression.
link |
We've talked about how some of the drugs
link |
that impact these different chemical systems might work
link |
and why they create some of the problems they create.
link |
The problems are mainly created by the fact
link |
that they impact lots of systems in the brain and body.
link |
So you take a drug to increase serotonin,
link |
but that serotonin is also related not just to mood,
link |
but to things related to libido and appetite.
link |
And so you start disrupting multiple systems.
link |
You know, the same could be said for behavioral tools,
link |
That any behavioral tool that adjusts the levels
link |
of a particular chemical ought to perhaps provide
link |
some relief for some of the symptoms of major depression.
link |
Let's take an example that I've talked about before
link |
on the podcast, which is,
link |
if you get into a very cold shower, you take an ice bath,
link |
you will release norepinephrine and epinephrine
link |
in your brain and body.
link |
There's no question about that.
link |
I don't think anyone can really escape that.
link |
It's a kind of a universal response to being in cold water.
link |
Well, if some aspects of depression are related
link |
to low levels of norepinephrine,
link |
will taking cold showers relieve your depression?
link |
It might even relieve certain aspects of that depression.
link |
Well, that's going to depend on the individual.
link |
Will exercise help?
link |
Well, if you go out for a run,
link |
you're going to increase the amount of norepinephrine
link |
If you enjoy that run,
link |
it's likely that you'll increase the levels of dopamine
link |
and probably serotonin in your brain and body as well.
link |
Will that cure your depression?
link |
Well, there are a lot of studies exploring how exercise
link |
can impact depression.
link |
And indeed, regular exercise is known
link |
to be a protective behavior against depression,
link |
but it also can help relieve some of the symptoms
link |
So you may ask yourself, why would you need drugs at all?
link |
Why would there be prescription drugs
link |
or the need for supplementation or other things
link |
to alleviate the symptoms of depression?
link |
Ah, well, that's the diabolical nature of depression,
link |
which is if people are far enough along in this thing,
link |
this sometimes called disease, sometimes called disorder,
link |
but major depression,
link |
oftentimes they can't get the energy
link |
to even get up and take a bath or a shower.
link |
They have no motivation to do it.
link |
They have no desire to go for a run.
link |
So you say, come on, let's go, you'll feel better.
link |
I know you feel better.
link |
It generates all these chemicals.
link |
I heard on the whatever podcast,
link |
Huberman Lab podcast or another podcast
link |
that getting into action does all these things
link |
and they just don't want to do it.
link |
And to you, a person who's not experiencing depression,
link |
that perhaps could just seem like the most frustrating
link |
and confusing thing in the world,
link |
but it's very important to highlight the fact
link |
that these circuits that are accessible to some of us,
link |
the circuits for happiness, for pursuit of pleasure,
link |
for exercise, for getting in a cold shower,
link |
if that's your thing,
link |
that those circuits are present in all people,
link |
but for certain people
link |
that are experiencing major depression
link |
and are really in the depths of their depression,
link |
they can't really access those circuits in the same way
link |
that people who are not suffering from depression can.
link |
So I hope that makes it clear.
link |
It's not offering any excuses for them.
link |
And indeed, I think those behaviors would help jolt them
link |
out of some of the symptomology of depression,
link |
but they're just not accessible to everybody.
link |
So let's talk about the things that people can do
link |
to deal with depression.
link |
And again, anytime you add a behavior or a tool
link |
or a supplement or subtract a behavior tool,
link |
supplement, drug, et cetera,
link |
you absolutely should talk to your physician,
link |
especially if you're somebody
link |
that's dealing with major depression.
link |
I want to focus on the stress system,
link |
and I'm not just going to tell you
link |
to get sunlight in your eyes and to get a good night's sleep,
link |
although I think everybody should do that
link |
on a regular basis, ideally every day.
link |
Talked about those ad nauseum on this podcast.
link |
They will help your sleep.
link |
They will help you alleviate stress.
link |
I think you should have tools to deal with stress
link |
in real time, et cetera.
link |
But let's look at depression from the standpoint
link |
of a deeper biological phenomenon,
link |
which is inflammation and the immune system.
link |
There's growing evidence now
link |
that many forms of major depression,
link |
if not all of them, relate to excessive inflammation.
link |
Now, inflammation plays an important role in wound healing.
link |
It is a positive aspect of our immune system,
link |
our ability to combat wounds, combat illnesses, et cetera,
link |
but inflammation gone unchecked,
link |
inflammation that lasts too long or is of too high amplitude,
link |
meaning too many anti-inflammatory or inflammatory cytokines
link |
and things of that sort in the body is bad.
link |
And there's decent evidence now
link |
that inflammation can lead to or exacerbate depression.
link |
And that if we want to control depression
link |
or limit or eliminate depression,
link |
that focusing on reducing inflammation
link |
and its associated pathways is a really good thing to do.
link |
And I think this is a really good thing
link |
for everybody to do regardless of whether or not
link |
you suffer from depression or not.
link |
And today we're going to talk about exactly
link |
how depression comes about through the inflammation pathway.
link |
So first of all, who are the major players
link |
in creating chronic inflammation in the brain and body?
link |
They are the inflammatory cytokines,
link |
things like IL-6, interleukin-6,
link |
things like tumor necrosis alpha, TNF alpha,
link |
things like C-reactive protein, all right?
link |
Not all of these are cytokines.
link |
You have interferons and your prostaglandins
link |
and a lot of these things.
link |
But when we are stressed, chronically stressed,
link |
our brain and various locations in the brain become inflamed
link |
because certain classes of cells,
link |
in particular those glial cells,
link |
the cells that are typically thought
link |
to just be support cells,
link |
those cells and their biochemistry
link |
and their dialogue with the neurons of the brain and body
link |
starts to become disrupted.
link |
I may have mentioned it earlier, I don't recall,
link |
but I certainly mentioned it in an earlier podcast
link |
that adrenaline, epinephrine,
link |
when it's released in the body,
link |
it doesn't cross the blood-brain barrier,
link |
but there are certain things
link |
that are able to cross the blood-brain barrier
link |
when we are stressed.
link |
Things like the E2 prostaglandins,
link |
those cross the blood-brain barrier
link |
and our blood and our brain,
link |
therefore our brain and our body can communicate
link |
because certain things can pass through this barrier
link |
we call the BBB or the blood-brain barrier.
link |
And also we have something called the glymphatic system,
link |
which is really a plumbing system
link |
that links the brain and body.
link |
It's the link between the immune system and the brain.
link |
Well, there is a set of actions that we can take
link |
in order to limit inflammation.
link |
And this has been shown in several quality
link |
peer-reviewed studies now to reduce inflammation
link |
and to relieve some, and in some cases,
link |
all of the symptoms of major depression.
link |
One of those approaches is to increase our intake
link |
of so-called EPAs or essential fatty acids.
link |
There's now a very long list of papers
link |
in quality peer-reviewed journals
link |
showing that when people ingest a certain level
link |
of EPA omega-3 fatty acids,
link |
the relief from depressive symptoms matches the SSRIs.
link |
That's incredible, right?
link |
That essential fatty acids could relieve symptoms
link |
of depression as well as some
link |
of the prescription antidepressants.
link |
Now, this doesn't necessarily mean you run off
link |
and stop taking your antidepressants
link |
if you've been prescribed them.
link |
Please don't do that.
link |
Please talk to your physician.
link |
And I should mention that some of these same studies
link |
have shown that increasing our intake
link |
of these essential fatty acids,
link |
in particular the EPA variety of omega-3s,
link |
can lower the effective dose of things like SSRIs,
link |
meaning if we required a 50 milligram
link |
or 40 milligram dose of fluoxetine,
link |
that one can get by on a lower dose
link |
and thereby perhaps not experience as many
link |
or as severe side effects
link |
by taking or supplementing with EPAs.
link |
Now, the threshold level seems to be about one gram,
link |
a thousand milligrams of EPA.
link |
So you will sometimes see on a bottle of krill oil
link |
or fish oil or any other source,
link |
even plant source or other source of EPA,
link |
that it's a thousand milligrams or 1200 milligrams.
link |
But what's really important to look at is
link |
whether or not there's more than a thousand milligrams
link |
of EPA, because the EPA in particular
link |
is what's important here.
link |
And actually, in exploring some of the literature
link |
on the effects of EPAs on cardiovascular health,
link |
as well as their effects on depression,
link |
there's some interesting dose dependent responses
link |
such that people who took anywhere from 400 milligrams
link |
to 5,000 milligrams of EPAs
link |
achieved a variety of different benefits
link |
and in some cases, some side effects,
link |
we'll talk about those.
link |
And it does seem that this thousand milligrams
link |
is the critical threshold for benefiting
link |
or getting some relief from depressive symptoms.
link |
But people who took two grams seem to do better.
link |
And in the cardiovascular health realm,
link |
there it's a little more complicated.
link |
Some studies point to a very positive effect
link |
on cardiovascular health by taking increasing amounts
link |
of EPA, others, not so much.
link |
The current data point to the fact
link |
that for every gram of EPA that one ingest,
link |
there's about a 9% improvement in cardiovascular health.
link |
The same dose dependent improvement on psychological health
link |
in combating depression can't really be stated.
link |
I wouldn't say that the more EPA you take,
link |
the better you're going to feel, so to speak.
link |
I don't think the data point to that.
link |
However, it does seem that if you take a gram,
link |
a thousand milligrams or 2000 milligrams of EPA,
link |
there does seem to be some substantial relief
link |
for many people, which I emphasize many, not all,
link |
for many people in major depressive symptoms.
link |
So how would this work?
link |
Well, it turns out that these inflammatory cytokines,
link |
they impact neurons and the circuits of the brain
link |
that relate to things like serotonin,
link |
dopamine, and norepinephrine.
link |
These inflammatory cytokines act in a variety
link |
of different ways, but they mainly act to inhibit
link |
the release of serotonin, norepinephrine, and dopamine,
link |
or the synthesis of serotonin, norepinephrine, and dopamine.
link |
And I'll give you one example of how EPAs
link |
can positively impact this process.
link |
And then it points to a second tool,
link |
which is the proper utilization of exercise
link |
to offset the effects of depression.
link |
So now you should understand why having healthy levels
link |
of serotonin is important for maintaining healthy mood.
link |
It's not responsible for all the aspects
link |
of having a healthy mood.
link |
There's also dopamine and norepinephrine,
link |
but it is a very important one.
link |
Dopamine, also called 5-HT,
link |
essentially derives from a precursor called tryptophan.
link |
Tryptophan arrives into our system through our diet, okay?
link |
Tryptophan is an amino acid.
link |
Tryptophan is found in turkey.
link |
It's found in carbohydrates,
link |
and that should therefore raise the idea of,
link |
hmm, I wonder if one of the reasons why people
link |
who are depressed have such an appetite for carbohydrate
link |
laden foods is because they're trying to get more tryptophan
link |
and therefore more serotonin.
link |
And indeed that's the case.
link |
Tryptophan is eventually converted into serotonin.
link |
However, if there's excessive amounts of inflammation,
link |
these inflammatory cytokines cause tryptophan
link |
to not be converted so much into serotonin,
link |
but to be diverted down a different pathway.
link |
The pathway involves something called IDO,
link |
idolamine, which converts tryptophan into kynurene, okay?
link |
Kynurene actually acts as a neurotoxin
link |
by way of converting into something called quinolinic acid,
link |
okay, and quinolinic acid is pro-depressive.
link |
So if that seems like a complicated biochemical pathway,
link |
what's basically happening here is that the tryptophan
link |
that normally would be made into serotonin
link |
under conditions of inflammation is being diverted
link |
into a neurotoxic pathway and ingestion of EPAs,
link |
because it limits these inflammatory cytokines,
link |
things like IL-6, C-reactive protein, et cetera,
link |
can cause more of the tryptophan that one ingests
link |
or has in their body to be diverted
link |
towards the serotonergic pathway.
link |
Exercise, it turns out, also has a positive effect
link |
on the tryptophan to serotonin conversion pathway.
link |
And the way it does it is really interesting.
link |
You now know that tryptophan can either be converted
link |
into serotonin or it can be converted into this neurotoxin,
link |
which is a bad thing.
link |
Exercise, the activation of the muscles
link |
through rhythmic repeated use,
link |
in particular aerobic exercise,
link |
but also resistance training has been shown to do this
link |
to some extent, tends to sequester or shuttle the kynurene
link |
into the muscle so that it isn't converted
link |
into this neurotoxin that is pro-depression, okay?
link |
There are a lot of steps in the pathway
link |
leading to depression, but what this essentially means
link |
is that hitting a certain threshold level of EPA intake,
link |
whether by supplementation with fish oil or krill oil
link |
or through some plant source,
link |
if you're not into ingesting fish or krill,
link |
or trying to get up above that 1,000 milligram threshold
link |
for EPA by ingesting particular food sources,
link |
you certainly can do it through food,
link |
you don't have to supplement,
link |
but it's easier to do with supplements,
link |
that doing that will limit the inflammation
link |
that diverts tryptophan into this neurotoxic pathway
link |
and exercise as well augments this conversion
link |
of tryptophan into serotonin because it takes this thing
link |
that would potentially be a neurotoxin and it sequesters it,
link |
it pulls it away so that it can't actually go have
link |
its pro-depressive effects.
link |
So you've got multiple steps here.
link |
We're describing two tools,
link |
increasing EPA and regular exercise
link |
as a way of increasing serotonin somewhat indirectly, right?
link |
It's by limiting this bad pathway
link |
to promote the activity of a good pathway.
link |
But from the data that are published
link |
in quality peer-reviewed journals,
link |
it really appears that this inflammation pathway
link |
does function to increase depression through these pathways.
link |
And so knowing that there are behavioral steps
link |
and supplementation-based steps,
link |
or if you prefer getting your EPAs from typical food,
link |
from nutritional approaches,
link |
I find that very reassuring that the mechanisms
link |
all converge on a common pathway, serotonin.
link |
That gives me great peace of mind that when people say,
link |
hey, go out and go out for a run
link |
or you should get outdoors, exercise,
link |
or you should take fish oil or like the Scandinavians,
link |
do I have Scandinavian family members?
link |
And they are known to,
link |
or I should say they are quite open about the fact
link |
that during the winter months in particular,
link |
when depression is more likely,
link |
but throughout the year, really,
link |
they make an effort to regularly ingest high levels of EPA,
link |
either through ingesting fatty fish and its skin.
link |
I'm not a particular fan of ingesting the skin of fatty fish
link |
or by supplementing with cod liver oil
link |
or other types of fish oil,
link |
sardines and things of that sort, sardine oils.
link |
There are a number of different things out there
link |
that one could use.
link |
So I find it very reassuring
link |
that there's a common biochemical pathway
link |
that can explain why these things not just work,
link |
but why they should work.
link |
They should work because they operate
link |
in the very same biochemical pathways
link |
that antidepressants that are prescribed to people do.
link |
So what does this mean for you?
link |
Well, if you're somebody who suffers from major depression,
link |
again, don't stop taking your prescribed medication,
link |
talk to your doctor,
link |
but talk to them perhaps about the EPAs and exercise
link |
and how these things can impinge
link |
on the same biochemical pathways.
link |
If you're somebody who's not suffering from major depression,
link |
I still think these pathways
link |
are really important to understand.
link |
And actually knowing these pathways
link |
is additional motivation to get regular exercise.
link |
I think we all know that we should be getting
link |
anywhere from 150 minutes to 180 minutes per week
link |
of so-called zone two cardio for cardiovascular effects.
link |
Zone two is the kind of mellowish cardio
link |
where you can sort of hold a conversation
link |
if you needed to, but it's a little bit tough.
link |
You're kind of sucking for air a little bit.
link |
And that's going to limit these depressive-like symptoms.
link |
I think in all of us,
link |
I don't think that we should think of depression
link |
as a strict threshold.
link |
I'm somebody who personally has made the choice
link |
to take 1,000 milligrams of EPA per day.
link |
I do that by supplementing fish oil.
link |
There's debate out there as to whether or not
link |
it's better to take EPA and DHA in particular ratios
link |
and whether or not DHA can impact the LDL,
link |
which is the so-called bad cholesterol.
link |
That's getting really down into the weeds,
link |
and we can talk about that in a future episode.
link |
But for myself, I notice a pretty substantial
link |
positive effect of taking anywhere
link |
from 1,000 milligrams to 2,000 milligrams of EPA per day.
link |
I do that through supplementation,
link |
and I do strive to try and eat some fish,
link |
even though, frankly, I've never liked the taste of fish.
link |
For those of you that would like a little more detail
link |
or perhaps a lot more detail into the effects of EPA
link |
on depression and in relieving depressive symptoms,
link |
and if you want to get into the nitty gritty of it,
link |
I invite you to go to examine.com, put in depression, EPA.
link |
They list off and have links to 28 studies
link |
on the effects of EPA on major depression.
link |
If you go to PubMed, there are many, many studies
link |
on this now that date back several decades, really.
link |
If you're interested in the specific effects of EPA
link |
as opposed to DHA, I want to point you towards
link |
a particular study entitled, not surprisingly,
link |
EPA, but not DHA, appears to be responsible
link |
for the efficacy of omega-3 long-chain polyunsaturated
link |
fatty acid supplementation in depression,
link |
evidence from a meta-analysis of randomized control trials.
link |
This is a really wonderful paper.
link |
The author is Julian Martins, M-A-R-T-I-N-S.
link |
It was published in 2009.
link |
We will provide a link to this study in the caption,
link |
and that study is really the one that, at least to me,
link |
points to why EPA in particular is what's effective,
link |
and that whether or not DHA is problematic or not
link |
is a separate issue, but it's really the EPA
link |
that one wants to hit a certain threshold level of
link |
if one's goal is to get relief from depression
link |
or to keep depression at bay by keeping mood elevated,
link |
which is why I take high-dose EPA.
link |
So we've got EPA, we've got exercise.
link |
Now you understand how they work to adjust mood.
link |
Now I want to talk about something that, at least for me,
link |
was quite surprising when I first learned about it
link |
for sake of treatment of mood disorders,
link |
and that's creatine.
link |
Creatine has a number of very important functions
link |
throughout the body.
link |
For those of you that are into resistance training,
link |
and actually for those of you
link |
that are into endurance training as well,
link |
creatine has achieved a lot of popularity in recent years
link |
because supplementation with creatine
link |
can draw more water into muscles
link |
and can increase power output from muscles.
link |
So it's something that does indeed work.
link |
There have been debates about whether or not
link |
it's unhealthy for the kidneys
link |
to take long-term creatine supplementation at high doses,
link |
and I invite you to go down that rabbit hole.
link |
I think most people now accept the idea that,
link |
for most people, not all, but for most people,
link |
low-dose creatine supplementation of anywhere
link |
from one gram to five grams per day
link |
can have a number of positive effects
link |
on physical performance.
link |
People with kidney issues, et cetera,
link |
need to be especially cautious,
link |
but creatine is interesting for that purpose.
link |
However, there's also a so-called
link |
phosphocreatine system in the brain,
link |
and that phosphocreatine system
link |
has everything to do with the dialogue
link |
between neurons and these other cell types called glia,
link |
and glia comprise several cell types,
link |
microglia, astrocytes, et cetera,
link |
but the phosphocreatine system
link |
in the forebrain in particular, in the front of our brain,
link |
has been shown to be involved in regulation of mood
link |
and some of the reward pathways, as well as in depression,
link |
and there are now several studies, at least three,
link |
although there are probably more by time this comes out,
link |
because they're coming out very quickly now,
link |
at least three quality studies pointing to the fact
link |
that creatine supplementation
link |
doesn't just have these positive effects
link |
on physical performance,
link |
but can also be used as a way to increase mood
link |
and to improve the symptoms of major depression.
link |
This has been now done
link |
in several double-blind placebo-controlled studies.
link |
These studies have looked at women,
link |
have looked at men, have looked at adolescents,
link |
some of whom were taking SSRIs, some of whom were not.
link |
They've done magnetic resonance spectroscopy,
link |
so spectroscopy is a way that you can look
link |
at the concentrations of particular compounds
link |
in the brain in real time in humans.
link |
It can be used for other things as well, of course,
link |
and basically what's been observed
link |
is that increasing the activity
link |
of the phosphocreatine system in the forebrain
link |
can be beneficial, or at least is correlated
link |
with improvements in mood.
link |
So let's just talk for a moment about what's involved
link |
with using or supplementing creatine
link |
in order to improve mood
link |
and perhaps even treat depression.
link |
First of all, when I talk about creatine,
link |
I'm talking about creatine monohydrate.
link |
There are a number of different forms of creatine.
link |
Here, I'm talking about creatine monohydrate.
link |
The American Journal of Psychiatry in 2012 published a study
link |
which was a randomized double-blind placebo-controlled trial
link |
of oral creatine monohydrate,
link |
and what it found is that it could augment
link |
or enhance the response
link |
to a selective serotonin reuptake inhibitor,
link |
in particular, in women with major depressive disorder.
link |
So like EPA, creatine supplementation seems
link |
to either lower the required dose of SSRI
link |
that's required to treat depression
link |
or can improve the effectiveness of a given dose of SSRI.
link |
However, there are other studies
link |
that have looked directly at creatine supplementation
link |
in the absence of SSRIs, and those are interesting as well.
link |
There's a wonderful and very comprehensive review
link |
on creatine for the treatment of major depression
link |
that includes beautiful tables of all the subjects
link |
and the dosages, et cetera.
link |
I'm not going to read off every line
link |
and every column in that review,
link |
but we will provide a link to that review as well.
link |
One of the things that's really striking
link |
about the lists of studies that they include is
link |
that most of them used dosages
link |
that are pretty reasonable for most people,
link |
anywhere from three grams to five grams,
link |
sometimes up to as many 10 grams per day of creatine.
link |
Many of these also were shown to increase activity
link |
of this phosphocreatine system in the forebrain,
link |
and some show a relationship
link |
between that phosphocreatine system
link |
and a particular category of receptors
link |
in the brain called the NMDA receptor,
link |
N-methyl-D-aspartate receptor.
link |
The NMDA receptor is one of the first things
link |
that every budding neuroscientist learns about
link |
because it is the receptor that has particular electrical
link |
and chemical properties that make it a critical gate
link |
for so-called neuroplasticity.
link |
So it's not a receptor that's activated in the brain
link |
typically for just the functioning of the brain
link |
on a day-to-day basis.
link |
It's a receptor that's activated
link |
when circuits are going to change,
link |
when they are inspired to change
link |
by some very strong stimulus, meaning some experience,
link |
or in some cases a drug, or in some cases something else.
link |
But the NMDA receptor is a kind of a key node
link |
for shifting brain circuitry.
link |
And so while the details aren't entirely clear,
link |
it seems that creatine supplementation leads to increases
link |
in the phosphocreatine system in the forebrain.
link |
And that increases in the activity
link |
of the forebrain phosphocreatine system relate to changes
link |
in the way the NMDA receptors function
link |
and may lead to some of the plasticity,
link |
the changes in neural circuits that underlie the shift
link |
from negative mood and affect to positive mood.
link |
Now, there are a lot of gaps.
link |
Those are, you know, there are a lot of little boxes
link |
or bins in the diagram I just laid out for you.
link |
And some of them are still truly black boxes, as we say,
link |
meaning we don't really know what's in them yet.
link |
And more mechanistic data are coming.
link |
However, when you look over the data in this review,
link |
or when I look over the data in this review,
link |
what you find is that there are pretty striking
link |
positive effects of creatine.
link |
And one of the more interesting effects is that
link |
creatine has actually been shown to increase mania
link |
in people that are already manic.
link |
And that's interesting.
link |
We're not talking about bipolar depression today,
link |
but it seems that creatine elevates levels of activation
link |
and kind of mood overall.
link |
And you could see why that would be a problem
link |
for somebody that's already in a manic phase,
link |
but it actually might be beneficial for somebody
link |
who is very low affect and has major depression.
link |
So should you supplement with creatine?
link |
Well, as always, talk to your healthcare provider.
link |
But if you're somebody who is thinking about things
link |
that you can do and things that you can take
link |
in order to improve your mood, keep depression at bay,
link |
maybe even support other treatments for major depression,
link |
the creatine system seems like a logical one.
link |
There's at least strong studies
link |
and a good number of them to look to
link |
to determine whether or not that's right for you.
link |
I personally take five grams of creatine for other reasons.
link |
I take it for the physical performance enhancing effects,
link |
but it's kind of nice to think that perhaps
link |
it's also helping me improve my mood.
link |
That's a choice that I've made for me
link |
as in within the margins of safety for me in my life.
link |
I don't know that it's right for everybody,
link |
but I find it very interesting.
link |
And again, I find it particularly interesting
link |
because there's a logical biochemical pathway
link |
to support the finding that it improves mood
link |
and can offset the effects of major depression
link |
in some cases, or can improve the effects
link |
of antidepressant medication in many cases.
link |
When I see mechanism and I see effectiveness
link |
and the mechanism and the effectiveness map
link |
to a lot of the same mechanisms
link |
that are involved in prescription drugs,
link |
that gives me great reassurance
link |
that this isn't just some sort of mysterious pathway
link |
or mysterious compound by which creatine might be working.
link |
So now we've clustered together EPA's exercise
link |
and their relationship to inflammation,
link |
creatine and its relationship to forebrain function
link |
and the phosphocreatine system and this NMDA receptor.
link |
And as you'll see in a few minutes,
link |
that NMDA receptor turns out to be vitally important
link |
and is actually one of the main nodes of action
link |
for some of the more novel and exciting therapeutics
link |
that are being explored now in psychiatric clinics.
link |
So let's talk a little bit more about this NMDA receptor
link |
and how it relates to some of the more experimental
link |
or novel therapeutic compounds
link |
for the treatment of major depression.
link |
And the compounds that we're going to be talking about,
link |
you may have heard of before,
link |
one is ketamine, which is getting increasing interest
link |
in psychiatric clinics and in various experimental
link |
and clinical studies, and the other is PCP.
link |
Both ketamine and PCP are known drugs of abuse.
link |
For many years, people have abused these drugs,
link |
go by the street name Special K, et cetera,
link |
and they create dissociative anesthetic states.
link |
So dissociative states where people don't feel
link |
as closely meshed with their emotions
link |
and their perceptions.
link |
It's an odd state, I hear, and it's an odd state
link |
that clinicians are now leveraging
link |
for the treatment of depression.
link |
We'll talk about why that is,
link |
but let's talk a little bit about this NMDA receptor
link |
and why ketamine and PCP might work
link |
for the treatment of depression or how they even could work.
link |
I want to be very direct that this is an area
link |
that still needs a lot of data.
link |
There are, however, some excellent papers
link |
from really terrific groups.
link |
One of them is a paper that was published
link |
in Nature last year, 2020.
link |
First author is Vesuna, Sam Vesuna, V-E-S-U-N-A,
link |
and the last author and the lead on the study
link |
was Dr. Karl Deisseroth, who was a guest
link |
on the Huberman Lab podcast a few months ago.
link |
He's a world expert in neuroscience.
link |
He's a psychiatrist, and this paper from Sam Vesuna
link |
and Karl and colleagues explored
link |
how these dissociative states come about,
link |
and they looked at this both in animals and in humans
link |
and found that there was essentially a common mechanism
link |
whereby a particular layer of cortex,
link |
so your brain has this outer shell of tissue
link |
that is called the neocortex.
link |
It's where our perceptions lie.
link |
It's where our associations lie.
link |
It's a very important area for processing,
link |
decision-making and planning, et cetera.
link |
It's literally stacks of cells,
link |
and one of those layers in the stack of cells is layer five,
link |
and the layer five neurons in particular
link |
went into a particular rhythm of electrical activity,
link |
this one to three hertz rhythm,
link |
after mice or humans were administered ketamine or PCP.
link |
There was activation of a particular area of the brain.
link |
This retrosplenial cortex, as it's called,
link |
and the dissociative state that emerged
link |
was an interesting one, and clinically what's described
link |
in the trials for ketamine and things like it,
link |
that people who are depressed will take ketamine,
link |
will experience a kind of separateness
link |
from their grief and from their emotions,
link |
and that possibly there's plasticity.
link |
There are actually shifts in the neural circuitry
link |
such that their emotions don't weigh on them so heavily.
link |
I'm using very loose language here,
link |
but that they don't feel as overridden
link |
or as burdened by their own emotions
link |
as they did previously to the ketamine therapy.
link |
Now, absolutely in no way, shape or form,
link |
in my suggestion that people run out and take ketamine
link |
in order to treat their own depression,
link |
these drugs are still very much experimental,
link |
although they are approved in certain contexts,
link |
at least in the US, by prescription
link |
for the treatment of depression.
link |
What's interesting to me is that these dissociative states
link |
sound, at least at the outset,
link |
to be more of a separateness from everything.
link |
It sounds a little bit like depression itself.
link |
It's sort of like anhedonia,
link |
an inability to experience pleasure,
link |
and then one takes a dissociative anesthetic
link |
and somehow is able to get relief
link |
by getting even further away from an experience.
link |
To me, that doesn't make sense,
link |
but that just speaks to the fact that these drugs
link |
and these receptors and these pathways
link |
operate through very cryptic means,
link |
and we really don't understand all the pathways in the brain
link |
that relate to motivation and mood and so forth.
link |
And the results with these ketamine trials
link |
are looking very promising.
link |
In fact, there are a number of trials that show
link |
that a fair number of people that take ketamine
link |
in a therapeutic setting legally
link |
with a psychiatrist guiding the experience
link |
are able to get relief from their symptoms
link |
without the need for many, many treatments with the drug.
link |
Just how many treatments varies
link |
from individual to individual,
link |
but it's not like people have to take this stuff ongoing.
link |
This is really an attempt to tap into this NMDA receptor
link |
that is related to neuroplasticity.
link |
Both ketamine and PCP essentially act as antagonists,
link |
which means they block the NMDA receptor.
link |
They do it through different methods,
link |
non-competitive and competitive
link |
for you chemists and pharmacologists out there.
link |
You can look it up if you like.
link |
But what's therefore even more surprising
link |
is that every neuroscientist learns
link |
that activation of the NMDA receptor,
link |
not antagonism or blocking of the NMDA receptor,
link |
leads to changes in neural circuitry in very profound ways.
link |
In fact, experimentally,
link |
and I've done these experiments myself,
link |
if you want to prevent plasticity,
link |
you want to prevent an experience
link |
from reshaping neural circuitry,
link |
you give an NMDA receptor blocker.
link |
I've done that many times
link |
in the course of my experimental neuroscience career,
link |
not to myself, obviously,
link |
but in the course of doing experiments.
link |
So it's still a bit mysterious to me how this could work.
link |
A couple of things,
link |
one is this layer five activation is pretty interesting.
link |
We're going to come back to layer five
link |
when we talk about yet another emerging treatment
link |
for depression, which is psilocybin,
link |
so-called magic mushrooms,
link |
and the effects of psilocybin
link |
on layer five neurons in the cortex.
link |
So there's a common theme emerging here,
link |
which is that layer five activity in the cortex
link |
may be important for rewiring the brain in certain ways
link |
that can lead to recovery or to an alleviation
link |
of some of the symptoms of major depression.
link |
So if this is sounding a little bit vague to you,
link |
it's because this is still truly experimental and new,
link |
and still very much on the cutting edge
link |
of what's happening now, we don't have all the answers.
link |
So if it sounds like I'm moving slowly through this
link |
and I'm being extra careful about what I say,
link |
you are correct, your antennae are correct in this case.
link |
I never want to misstep and say something that's not true,
link |
but that's especially the case
link |
when we're talking about experimental therapies and drugs,
link |
which formerly were taken as drugs of abuse,
link |
which are now being used as drugs
link |
for therapeutic treatment in the clinic.
link |
There is a very interesting study.
link |
This was published in Science in 2019.
link |
So these are very recent studies.
link |
The last author on this is Liston, L-I-S-T-O-N.
link |
The title of the paper is
link |
Sustained Rescue of Prefrontal Circuit Dysfunction
link |
by Antidepressant-Induced Spine Formation.
link |
And here, when we hear spine,
link |
we're not referring to spine as in your vertebrae
link |
running down your spinal column.
link |
We're talking about the spines,
link |
which are these little protrusions on neurons.
link |
Neurons are not smooth by any stretch.
link |
If you zoom in on a neuron,
link |
if you were to come to my lab
link |
and look down the microscope at a neuron and zoom in on it,
link |
you'd find that some neurons are smooth,
link |
but most neurons have these little protrusions
link |
and those little protrusions are called spines.
link |
And those little spiny protrusions are little sites
link |
where neurons can reach out and form and receive
link |
new synapses from neighboring neurons.
link |
So they increase the surface area of a neuron
link |
and allow new connections to be formed.
link |
And so spine formation is synonymous with neuroplasticity,
link |
which is synonymous with changes in circuit function,
link |
which is synonymous with changes in the ways that we think,
link |
we feel, and we behave.
link |
And what was shown in this study is really interesting.
link |
What they showed is that ketamine
link |
can relieve depressive symptoms rapidly
link |
by changing or increasing in this case,
link |
the spines on these neurons in the prefrontal cortex.
link |
And if that word prefrontal rings a bell,
link |
well, now you remember the phosphocreatine system,
link |
the ingestion of creatine monohydrate
link |
and the forebrain, activation of the forebrain
link |
were related to in some way or another to relief
link |
or improvement of major depressive symptoms.
link |
So we're starting to converge on a picture here
link |
whereby these drugs, ketamine, PCP,
link |
used in a therapeutic context,
link |
maybe increasing neuroplasticity,
link |
literally the changing of neural circuits in the forebrain
link |
somehow through dissociative states.
link |
And I don't want to speculate too much
link |
about how that might come about,
link |
but one of the things that such a resounding
link |
or repeating theme of major depression
link |
is that when you talk to somebody who has major depression,
link |
it is a real downer.
link |
And I'm not being disparaging of those people,
link |
but if you've ever had a conversation
link |
with someone who's depressed,
link |
they're always talking about how exhausted they are,
link |
or in really severe cases,
link |
they are not even responsive at all.
link |
They just kind of stare at you blankly or they fall asleep.
link |
I mean, they're truly depressed.
link |
Their system is lowered in terms of its activation state.
link |
So I think that it's interesting
link |
that the application of drugs
link |
that allow people to separate from that state
link |
of not caring or being uninterested
link |
or unwilling to do anything
link |
is actually one of the paths to treatment.
link |
It's not always about just getting people peppy
link |
and excited and happy.
link |
There also seems to be a requirement
link |
for getting them distanced from their own grief.
link |
And this brings us back to something that we talked about
link |
way back at the beginning of this episode,
link |
which was this particular feature
link |
of the anti-self confabulation,
link |
that everything that happens is a reflection
link |
that I should say for the depressed person,
link |
that everything that happens is a reflection
link |
of how life is bad and their experiences
link |
just point to the fact that nothing is going to get better.
link |
This is the common language of depression.
link |
If this is very depressing to hear me talk about,
link |
it is heavy, and that's what it's like to hear these things.
link |
It's even heavier, of course,
link |
for somebody to experience them.
link |
And those beliefs, those patterns of guilt and grief
link |
and anhedonia and delusional anti-self confabulations,
link |
those are the things that eventually,
link |
if they get severe enough,
link |
start to convert into things like self-harm, mutilation,
link |
and in the most tragic of cases, of course, suicide.
link |
And so I think we can look to these treatments
link |
such as ketamine and PCP,
link |
but in particular ketamine and its use in the clinic
link |
as ways for people to get distanced
link |
from the negative affect that they feel
link |
isn't just inside them or overwhelms them,
link |
but that for the very severely depressed person,
link |
they feel is them.
link |
And we hear this sometimes, you are not your emotions.
link |
That's a statement that I've always been
link |
a little bit challenged by.
link |
I mean, yes, indeed, emotions are not who we are.
link |
They are states that we go into and out of,
link |
including happiness and sadness,
link |
but they are very much a part of us
link |
when we experience them.
link |
We don't experience them as next to us or behind us
link |
or across the room from us.
link |
We experience them as our emotions.
link |
They are so much part and parcel
link |
with our experience of ourself
link |
that a statement like we aren't our emotions
link |
is a very hard statement to digest,
link |
especially for the depressed person.
link |
And so I think that the NMDA receptor
link |
and its capacity to induce neuroplasticity circuit changes,
link |
the fact that PCP and ketamine
link |
are both showing activation of neural circuits
link |
by way of suppressing activity of the NMDA receptor
link |
and some of the positive or exciting therapeutic outcomes
link |
that are coming from this
link |
really point to the fact that ketamine and PCP
link |
and removal of negative experiences
link |
or the experience of a negative experience,
link |
it's sort of getting meta there,
link |
but the experience of a negative experience
link |
may be an important path by which
link |
people treat their depression,
link |
especially in its most severe forms
link |
where people are veering towards
link |
self-harm, mutilation, and suicide.
link |
So you may have noticed a theme,
link |
which is that certain categories of approaches
link |
that we've been discussing
link |
for offsetting the symptoms of depression,
link |
such as exercise, ingesting EPAs,
link |
reducing inflammation,
link |
or even the SSRIs for increasing serotonin,
link |
focus on changing some core biological function,
link |
like raising the amount of a chemical, serotonin,
link |
or reducing the amount of inflammatory cytokines
link |
in the brain and body.
link |
And yet things like ketamine
link |
focus more on rewiring circuitry,
link |
changing neural circuitry
link |
so that it functions better in the immediate
link |
and hopefully in the long-term as well,
link |
and keep people with major depression
link |
in what they call remission,
link |
away from major depression.
link |
Another category of treatments
link |
that's being actively explored now in laboratories
link |
and in the psychiatry realm are the psychedelics.
link |
And that's a huge category of compounds.
link |
However, one in particular, psilocybin,
link |
is one that's being most intensely and actively pursued
link |
for its capacity to treat major depressive disorder.
link |
I want to be very clear
link |
that the work that I'm going to describe
link |
is work that's being done in university settings,
link |
university hospitals, by scientists and psychiatrists.
link |
And these are clinical studies, clinical trials,
link |
leading to peer-reviewed data.
link |
And those are the data that we'll be discussing.
link |
Some of the major luminaries in this area include,
link |
of course, aren't limited to,
link |
but include people like Matthew Johnson,
link |
who's at Johns Hopkins.
link |
We'll discuss some of his work now.
link |
And fortunate to say that he will be coming on the podcast
link |
as a guest to describe the studies
link |
in a variety of laboratories,
link |
working on a variety of different psychedelic compounds.
link |
But let's focus on psilocybin
link |
for its capacity to rewire neural circuits
link |
and alleviate depression.
link |
There have been anecdotal data or evidence over the years
link |
that psilocybin has this capacity.
link |
How does psilocybin work?
link |
Well, psilocybin magic mushrooms, as it's sometimes called,
link |
mainly works on what's called the serotonin 5H2A receptor
link |
with some affinity for the 5HT1 receptor.
link |
What does that mean?
link |
Well, basically you've got a lot of different kinds
link |
of serotonin receptors,
link |
just as you have a lot of different kinds
link |
of dopamine receptors or other types of receptors.
link |
The advantage of having different receptors
link |
expressed in different parts of the brain and body,
link |
even on different parts of individual cells
link |
in the brain and body,
link |
is that the same compound serotonin
link |
can have a diverse set of effects
link |
on different cells and tissues.
link |
This is also the basis of some of the side effect profiles
link |
of SSRIs, because maybe, for instance,
link |
we know that taking Prozac fluoxetine
link |
will increase serotonin in one area,
link |
but also in another area,
link |
and then they will go have diverse effects
link |
on different brain circuits
link |
because of the variety of receptors.
link |
Receptors are just like parking slots
link |
where the molecule serotonin parks
link |
and has different effects.
link |
Well, psilocybin engages or increases serotonin transmission,
link |
meaning it increases the amount of serotonin,
link |
mainly by acting at these 5H2A receptors,
link |
but where in the brain does it happen
link |
and what are the major effects?
link |
First, let's talk about the major effects,
link |
because I think that's what people are interested in.
link |
The study that I'd like to highlight
link |
is a fairly recent one.
link |
It was published in May of 2021
link |
in Journal of the American Medical Association Psychiatry,
link |
so JAMA Psychiatry,
link |
and it's entitled Effects of Psilocybin-Assisted Therapy
link |
on Major Depressive Disorder, a Randomized Clinical Trial.
link |
It's an absolutely beautiful study, a very important study.
link |
It includes some of the luminaries in this area,
link |
like Matthew Johnson, Patrick Finnan, Roland Griffiths,
link |
We will provide a link to this study.
link |
It is available in its full form at zero cost
link |
if you want to read it.
link |
It's got a lot of details,
link |
so I'm just going to summarize a few things,
link |
but basically what they did was they screened for patients
link |
to come into the clinic.
link |
These were people that suffered
link |
from major depressive disorder
link |
and administered either one or two rounds of psilocybin.
link |
They used particular dosages that are listed in the study,
link |
so you can look it up
link |
if you're really interested in that level of detail.
link |
Typically, it was 20 milligrams per kilogram of body weight,
link |
so it depends on body weight,
link |
or 30 milligrams of psilocybin
link |
per 70 kilograms of body weight.
link |
They were given in capsule form,
link |
so people weren't eating the mushrooms.
link |
This is obviously a very controlled study,
link |
and they want to control the dosages appropriately.
link |
They were randomized to begin the treatment immediately
link |
or after an eight-week delay.
link |
They had all the appropriate control groups
link |
that one would like to see.
link |
What's really striking about this study
link |
is that there was a very significant improvement
link |
in mood and affect and relief from depressive symptoms
link |
in anywhere from 50 to 70% of the people
link |
that were subjects in the study
link |
who received the psilocybin treatment.
link |
And whether or not it was 50 or whether or not it was 71%
link |
varied according to how long after the study
link |
they maintained these antidepressant effects,
link |
whether or not they stayed in remission from the depression.
link |
But these are really enormous and significant effects,
link |
very exciting, and are pointing in the direction
link |
of psilocybin very soon becoming a treatment
link |
for various forms of depression,
link |
including major depression.
link |
Now, of course, this is limited to the laboratory at present.
link |
There are a number of elements of these studies
link |
that are important to take into consideration too,
link |
which is that there are highly trained guides,
link |
meaning people to direct people through the experience.
link |
As Matthew Johnson has told me,
link |
there is the occurrence from time to time
link |
of people having so-called bad trips,
link |
of having anxiety attacks during the hallucinations
link |
and all that, and they have ways to mitigate that
link |
and deal with that because the guides are trained.
link |
They have all the sorts of medical monitoring devices
link |
for heart rate and temperature and things that one
link |
would like to see for a study like this,
link |
because these are very powerful compounds.
link |
I don't want to give away any elements of the discussion
link |
with Matthew Johnson because it will be released
link |
in podcast form reasonably soon here,
link |
the Huberman Lab podcast.
link |
But one of the things that came up
link |
and is a fundamental question that I had
link |
that I think probably many of you are asking is,
link |
does the experience that one has on these compounds
link |
make a difference for whether or not somebody
link |
gains relief from depression
link |
from these psilocybin journeys or not?
link |
In other words, does it matter what they talk about?
link |
Does it matter what they think about?
link |
Does it matter if they have a good trip or a bad trip?
link |
And I don't want to hold you in too much suspense.
link |
I'll let Matthew provide the more thorough answer,
link |
but what's really interesting is there are some common
link |
themes to psilocybin administration and experience
link |
that lead to relief from depressive symptoms,
link |
but they are subjectively, excuse me, subjectively
link |
very varied, meaning that whether or not people feel
link |
they had a good experience or a bad experience,
link |
whether or not people thought about their parents
link |
or thought about the color of the ceiling
link |
doesn't seem to have too much of an impact
link |
on whether or not they receive relief
link |
during these studies, in these clinical studies.
link |
It seems like different people can have lots
link |
of different experiences and still receive benefit.
link |
And that points to something deeper.
link |
It points to the fact that these drugs,
link |
which is really what they are,
link |
are rewiring neural circuitry in a common way
link |
despite a diversity of experience while on the drug.
link |
And that itself is really interesting.
link |
And it takes us back to a place that we've been before
link |
in this discussion, which is layer five of the cortex,
link |
this area that ketamine seems to impact as well
link |
by generating rhythms of, I mentioned one to three hertz
link |
activity in layer five of certain areas of the cortex.
link |
Well, the 5-HT1A receptor is known to be enriched
link |
in layer five of the cortex.
link |
And layer five of the cortex is a very interesting area
link |
because it's an area in which there's a lot
link |
of lateral connectivity.
link |
So connections between different brain areas laterally
link |
generally is what allows us to merge different senses.
link |
So for instance, when we hear a sound off to our right,
link |
over here, we turn to our right,
link |
there's a very hardwired response.
link |
And typically we hear something off to our right,
link |
we don't look to our left.
link |
That's how hardwired some of these circuits are.
link |
What appears to be happening is that the activation
link |
of the serotonin system in 5-HT1A receptor in layer five
link |
is offering up or providing an experience
link |
whereby the lateral connections are able to engage
link |
much more broadly than they would normally.
link |
Now that also could be a bad thing.
link |
And I asked Matt about this, that sounds kind of spooky.
link |
I don't know that when I hear something off to my right
link |
that I want to look off to my left,
link |
that could be highly maladaptive,
link |
especially if it's a car coming at me from my right.
link |
That doesn't seem to be what's happening.
link |
It's not really rewiring these deeply reflexive circuits.
link |
It's somehow rewiring associations between events,
link |
emotional events, past events, current events,
link |
and future events in ways that allow people
link |
to get some sort of relief or distance
link |
from these narratives, these depressive stories
link |
about their past and present,
link |
and allow them to see new opportunity
link |
and optimism in the future.
link |
That's really a fascinating thing
link |
if you really think about it,
link |
because I would have thought that simply
link |
by ramping up laterality of connections,
link |
meaning the cross associations,
link |
that things could either be rewired randomly
link |
in ways that don't serve us,
link |
or would perhaps just cause no effect at all.
link |
So it's either going to be bad or neutral,
link |
but that's not really the way things are turning out.
link |
Again, these are highly controlled studies.
link |
I do want to emphasize that ketamine, psilocybin,
link |
these things are still illegal, most all places.
link |
There are some regions and cities in the United States
link |
where they are locally decriminalized,
link |
but they are not legal.
link |
They're still illegal.
link |
So what we're referring to here are indeed clinical studies
link |
in which people are taking them legally.
link |
I think it's very likely we will see a shift
link |
in the legislature around psychedelics,
link |
and in particular psilocybin in the not too distant future.
link |
And I think that for now,
link |
what we should know is what Matt told me
link |
and what you'll hear far more about,
link |
which is that psilocybin, this one,
link |
or in most cases, two dose treatments done
link |
in a highly clinical setting, controlled setting,
link |
with patients that are carefully selected,
link |
can in many cases, the majority of people receive
link |
and maintain relief from their depressive symptoms
link |
simply through the experience of this psychedelic journey.
link |
I did ask him about microdosing.
link |
I made it sound as if I had never heard about it before.
link |
Microdosing, not microdosing, microdosing.
link |
And his answer was interesting.
link |
His answer was that the microdosing effects
link |
don't seem to be nearly as impactful as some of these,
link |
let's just call them what they are,
link |
these kind of high amplitude sessions
link |
that there are just one or two.
link |
There are some studies ongoing where there's more than two,
link |
but that the microdosing doesn't seem to compare
link |
to these macrodosing, I mentioned the dosages before,
link |
this 20 milligrams per 70 kilograms
link |
or 30 milligrams per 70 kilograms dosages
link |
given several weeks apart.
link |
So you'll hear more about microdosing and other psychedelics
link |
and their impact on depressive states
link |
and major depression in the episode with Matt.
link |
But for the time being, it really seems as if,
link |
again, we're looking at neuroplasticity,
link |
we're coming back to layer five,
link |
just like with ketamine and PCP,
link |
we're hearing about layer five,
link |
we're hearing about rewiring of circuitry,
link |
we're hearing about a dissociation
link |
or a distancing of oneself from these negative moods
link |
and affects and narratives,
link |
but there's a key distinction between the ketamine work
link |
and the psilocybin work,
link |
which is that in the ketamine work,
link |
it really is about dissociating from experience
link |
during the session with the psychiatrist,
link |
whereas during the psilocybin journey,
link |
it's really about immersing oneself in the experience
link |
and being fully present to that experience.
link |
That does seem to be an important component
link |
and what the difference is there
link |
and why they both seem to provide some relief
link |
from major depression
link |
I think most likely it takes us back to the fact that
link |
this thing we call major depression clearly involves
link |
serotonin, dopamine, and norepinephrine,
link |
and in some individuals,
link |
they may be more deficient in one or several of those
link |
or all of those, whereas in other individuals,
link |
it might be a different collection of chemicals.
link |
And of course, there are a tremendous number
link |
of other psychedelic compounds that people are exploring
link |
for treatment of major depression,
link |
but really psilocybin is the one
link |
that we have the most data on.
link |
MDMA has mainly been explored in the clinical realm
link |
for treatment of trauma.
link |
There are some trials ongoing for treatment of depression,
link |
but the big breakthroughs seem to be happening
link |
in the realm of trauma treatment,
link |
the so-called MAPS group that's doing this,
link |
again, legally in a clinical setting.
link |
And there are other groups
link |
that are starting to do it as well.
link |
We are going to do an entire podcast episode
link |
about MDMA and some related compounds,
link |
so I'll save that discussion for then.
link |
One of the most common questions I get for this podcast
link |
is about different diets, different regimes,
link |
different nutritional plans,
link |
things like keto, ketogenic diet, or vegan diets,
link |
or intermittent fasting, or the all-meat diet,
link |
the so-called lion diet, et cetera.
link |
There are actually really interesting data
link |
relating nutrition and diet to major depressive disorder.
link |
And I think we just need to frame this
link |
by returning to something that was said earlier,
link |
which is that the ingestion of carbohydrates,
link |
in particular carbohydrates and some meats like turkey
link |
that are rich in tryptophan, this precursor to serotonin,
link |
are in many ways the self-medicating version
link |
of depression treatment.
link |
Now, to be clear, I'm not saying that people should use food
link |
to medicate their depression.
link |
Many people do that reflexively, however.
link |
They reach for carbohydrate-rich foods
link |
to blunt their cortisol,
link |
because that's indeed what it does.
link |
It blunts cortisol when you ingest high-carbohydrate foods,
link |
in particular starchy foods,
link |
and it does increase serotonin,
link |
in particular if those foods, rather,
link |
are rich in the amino acid tryptophan.
link |
Now, ingesting food is wonderful and important and great,
link |
but ingesting excessive foods of any kinds,
link |
carbohydrate or otherwise, is not healthy, of course.
link |
There have been some explorations
link |
of whether or not a vegan diet
link |
can improve symptoms of depression.
link |
Not a lot of data, not impressive data.
link |
There have been very few controlled studies
link |
looking at the carnivore all-meat diet.
link |
On that, I think there are now some
link |
that are starting to spin up,
link |
meaning the studies are starting to spin up.
link |
However, the ketogenic diet has been explored
link |
for its ability to relieve certain symptoms of depression,
link |
in particular to what's called maintain euthymia.
link |
Euthymia is the kind of state of equilibrium
link |
between a manic episode and a depressive episode
link |
in a manic bipolar person.
link |
We'll return to this more in a future episode.
link |
But basically, manics have highs and they have lows.
link |
Bipolars either cycle back and forth really quickly,
link |
so rapid cycling, bi-polars, or slope.
link |
Some people, so really quickly can be day-to-day.
link |
Other people, it's month-to-month or week-to-week.
link |
They're going highs and lows.
link |
And you hear about mania and you hear about dysphoria.
link |
Euthymia is that kind of place in the middle
link |
where people feel neither too high nor too low.
link |
And there are some interesting studies
link |
looking at the ketogenic diet
link |
for maintaining euthymia in manic depressives,
link |
but also in people with major depressive disorder.
link |
Why would this work?
link |
Well, we have to remember that the ketogenic diet
link |
wasn't discovered so that self-appointed nutrition gurus
link |
could talk about it online,
link |
or so that people could make money
link |
selling anything related to ketosis.
link |
And here, I'm not disparaging of the ketogenic diets.
link |
Helped a lot of people.
link |
The ketogenic diet was actually shown
link |
to be medically relevant for its use to treat epilepsy.
link |
It turns out that in epilepsy,
link |
or in particular pediatric epilepsy,
link |
that a ketogenic diet and the shift of brain metabolism
link |
to predominantly one in which ketones are being metabolized
link |
rather than more standard glucose type metabolism
link |
can greatly reduce the number of epileptic seizures
link |
that these children experience.
link |
It's not always the case, but it's often the case.
link |
And so you talk to a neurologist or a neurosurgeon
link |
who's specialized in epilepsy,
link |
in particular pediatric epilepsy,
link |
and they'll tell you this,
link |
oh yeah, the ketogenic diet, in many cases,
link |
not all can be very effective for this treatment.
link |
How is it that a ketogenic diet reduces seizures?
link |
Well, the way it reduces seizures
link |
is by increasing what's called GABA transmission.
link |
GABA is a substance that is naturally released in our brain.
link |
It's an inhibitory neurotransmitter,
link |
meaning that when it's released into the synapse,
link |
it has the tendency to reduce the firing,
link |
to reduce the electrical activity of the next neuron
link |
or sets of neurons.
link |
There are various compounds that increase GABA,
link |
in particular, GABA in the forebrain.
link |
One common example would be something like alcohol.
link |
Drinking an alcoholic drink or two
link |
will increase GABA transmission,
link |
will ironically will lower your social inhibitions
link |
by increasing your neurochemical inhibition.
link |
It basically suppresses the self-monitoring pathways.
link |
And if people drink enough, it will suppress all pathways
link |
and people will urinate themselves and fall over.
link |
It will eventually inhibit all sorts of pathways.
link |
So the GABA system has a rich array of effects
link |
all over the brain and body,
link |
but alcohol tends to activate the release of GABA.
link |
You might say, well, then why not just take alcohol
link |
to suppress seizures?
link |
Well, that would be a terrible idea
link |
because there tends to be a rebound excitability
link |
after alcohol stops having its effects
link |
on the GABA receptors.
link |
And so then there's an excitability
link |
for which an epilepsy would be terrible.
link |
The reason why the epileptic diet is useful for epilepsy
link |
is that increases the, what we call the tonic level,
link |
the sort of the tide, the level of GABA in the brain,
link |
and that suppresses some of the hyperexcitability
link |
that is the characteristic feature of epilepsy.
link |
And there are other drugs, for instance,
link |
the benzodiazepines and things of the Xanax variety,
link |
Valium and so forth, those increase GABA transmission.
link |
Those drugs also have a lot of potential
link |
for abuse and addiction, et cetera.
link |
And they're problematic for other reasons.
link |
But the ketogenic diet,
link |
by way of increasing ketone metabolism
link |
or shifting brain's metabolism over to ketones,
link |
tends to modulate GABA such that GABA is more active
link |
and adjust the so-called GABA glutamate balance.
link |
This is getting technical,
link |
but glutamate is an excitatory neurotransmitter.
link |
GABA is inhibitory neurotransmitter
link |
and their balance is vital for neuroplasticity,
link |
for maintaining healthy levels of activity in the brain,
link |
And so there is decent evidence
link |
that people with major depressive disorders,
link |
in particular, the people with major depressive disorders
link |
that are refractory, meaning they don't respond
link |
to classical antidepressants, can benefit, it seems,
link |
from the ketogenic diet.
link |
Now, this is not always the case,
link |
but for those of you out there
link |
who are struggling with major depression
link |
and for which drugs have not worked,
link |
please talk to your psychiatrist.
link |
I don't know how many of them are up on the literature
link |
about the ketogenic diet or the EPAs and the rest.
link |
Psychiatrists vary in terms of how involved
link |
in the current literature they tend to be,
link |
but there are many excellent psychiatrists out there.
link |
Most of them, in my experience,
link |
are actually quite avid learners about what's happening
link |
and what's new in this realm that they call psychiatry.
link |
So it's really interesting that eating
link |
in a particular way, lowering carbohydrates
link |
to the point where you rely on ketogenic metabolism
link |
in the brain, increases GABA,
link |
and can provide some relief for depressive symptoms,
link |
and that in particular, that seems to have positive effects
link |
in people that are refractory
link |
or don't respond to classic antidepressants,
link |
and that would include things like fluoxetine, et cetera.
link |
I'll make one final point about ketogenic diets
link |
and GABA and depression,
link |
which is that it's also been shown that for people
link |
that respond well to these drugs
link |
that impact the serotonin system, dopamine system,
link |
or norepinephrine, the ketogenic diet there
link |
may improve the ability for those drugs
link |
to work at lower dosages,
link |
which is reminiscent of what we saw
link |
with the EPA supplementation.
link |
So today we've covered what at least feels to me
link |
like a tremendous amount of material.
link |
This topic of depression is indeed an enormous topic
link |
to try and get our arms around.
link |
We talked about the symptomology,
link |
we talked about some of the underlying neurochemistry
link |
and biology, and then we talked about approaches
link |
to deal with it that are really grounded
link |
in the neurochemistry and biology.
link |
I just want to recap a few of those tools
link |
and what those things are.
link |
First of all, we talked about making the effort
link |
to not overwhelm the pleasure system.
link |
That might seem counterintuitive,
link |
to not overly seek out pleasure
link |
or else one can find themselves in a place of depression.
link |
I mentioned way back at the beginning of the episode,
link |
a young man who I know to be really struggling
link |
with depression and it is thought,
link |
and we don't know for sure,
link |
but it is thought that some of that depression
link |
was probably triggered by an overindulgence in video games
link |
and other highly dopaminergic activities
link |
to the point where those activities eventually were countered
link |
by the pain balance that Dr. Anilemke described.
link |
And he now has to do those activities repeatedly
link |
and for many, many hours each day just to feel okay,
link |
not even to derive pleasure from them.
link |
And worse, many other activities,
link |
practically all other activities have lost their zest,
link |
they've lost their excitement
link |
and his sense of pleasure for them.
link |
And so there's a really active campaign now
link |
to reset that system.
link |
So number one, don't overwhelm your pleasure centers,
link |
either through activities or compounds.
link |
It might seem counterintuitive,
link |
but you're setting yourself up for anhedonia and depression
link |
It's not just about addiction, that too,
link |
but it's also about setting yourself
link |
for anhedonia and depression.
link |
How often can you engage in these activities?
link |
Well, that's going to differ from person to person,
link |
everyone's slightly different,
link |
but you should really mind your extreme highs
link |
and your extreme lows and be cautious about those.
link |
We'll probably have Dr. Lemke on again at a future time
link |
to try and get some more specifics about that.
link |
But if you do feel like you need to reset that system,
link |
it really does seem like a 30-day complete detox
link |
from whatever activity or substance that is,
link |
and ideally it doesn't continue after that 30 days,
link |
especially in conditions of drugs of abuse.
link |
Second of all, talked about the norepinephrine system
link |
and how the norepinephrine system is really deficient
link |
in many forms of major depression and in depression.
link |
There is now more deliberate pursuit
link |
of norepinephrine-inducing activities that are healthy,
link |
that aren't adrenaline-seeking per se,
link |
things like cold showers,
link |
things like particular patterns of breathing
link |
that engage and tend to make us more alert,
link |
things like exercise that will increase
link |
our levels of noradrenaline.
link |
I'd be remiss if I said that these activities
link |
could completely eliminate depressive symptoms
link |
in people with major depressive disorder.
link |
I don't think that's the case.
link |
And again, I want to acknowledge
link |
that people with major depressive symptoms
link |
often don't have the energy, the willingness,
link |
or the capacity to engage in some of these activities,
link |
but things like cold showers, deliberate cold showers,
link |
things like regular exercise,
link |
they aren't just feel-good activities.
link |
They actually engage the norepinephrine system
link |
and keep that system tuned up
link |
and allow us to increase our norepinephrine levels at will
link |
on a regular basis.
link |
And their mood-enhancing effects are real effects
link |
that at the level of neurochemistry.
link |
Then we talked about EPAs, these essential fatty acids,
link |
and it's clear that for most people,
link |
getting above 1,000 milligrams
link |
and probably even closer to 2,000 milligrams per day of EPAs
link |
can be beneficial for mood,
link |
especially in attempts to treat
link |
or offset major depressive disorder.
link |
Are there side effects?
link |
Well, you need to explore those for yourself
link |
and with your doctor.
link |
Everyone has a different health background.
link |
You know, for the margins of safety for most people
link |
will probably be quite large,
link |
but for some people that might not be the case.
link |
So definitely check with your physician.
link |
We also talked about exercise
link |
and how EPA and exercise on a regular basis
link |
can offset these inflammatory pathways.
link |
I want to mention something
link |
I've mentioned on a previous podcast,
link |
but in terms of keeping the inflammatory,
link |
all these molecules that create inflammation
link |
and then the inflammation can limit the amount of serotonin
link |
through the pathways we described.
link |
In order to do that, it's also very, very useful
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to ingest two to four servings of fermented foods
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on a daily basis or near daily basis.
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These are data that were published by the Sonnenberg Lab
link |
at Stanford recently in the journal Cell,
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Cell Press Journal, excellent journal,
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that ingestion of these fermented foods
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really keeps the gut microbiome tuned up, so to speak,
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well in order to offset these inflammatory cytokines,
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keeping inflammation at bay.
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It just turns out to be a really good thing
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in order to keep our mood in a good place.
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So EPA, exercise, fermented foods,
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creatine as a potential source of relief from depression
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or offsetting or keeping us away from major depression
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or relapse into depression.
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And then we talked about the prescription compounds
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and the compounds that are being used
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mainly in the course of studies
link |
and of psychiatry and depression,
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things like ketamine, PCP, psilocybin and related compounds.
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And then lastly, we talked about ketosis,
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which may not be right for everybody,
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but might be right for certain individuals out there
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who are grappling with this.
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If you're learning from this podcast
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and hopefully enjoying it
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and applying some of the tools that we describe,
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please subscribe to the podcast on YouTube.
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That really helps us.
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As well, please leave us a comment and some feedback
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for future episodes and topics
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that you'd like to see us cover.
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You can do that on YouTube in the comment section.
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As well, please follow us on Instagram.
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It's Huberman Lab on Instagram there.
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I provide some recaps of some of this material.
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I also provide some original material
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that doesn't show up in the podcast.
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Please also subscribe on Apple and Spotify
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if you haven't already.
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And on Apple, you have the opportunity
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as well as a comment and some feedback.
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Please also check out the sponsors
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that we mentioned at the beginning of the podcast.
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So that's a terrific way to support what we're doing.
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We also have a Patreon.
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It's patreon.com slash Andrew Huberman.
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And there you can support the podcast
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at any level that you like.
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Throughout the course of today's episode
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and in previous episodes, I mentioned supplements.
link |
That may be appropriate for you.
link |
If you want to check out the supplements that I take,
link |
you can go to thorn.com slash the letter U slash Huberman.
link |
That's T-H-O-R-N-E.com slash the letter U slash Huberman.
link |
There, you can see the supplements I take.
link |
If you want to try any of those supplements,
link |
you can get 20% off any of those supplements.
link |
And if you navigate from that location in the website
link |
to any other locations in the Thorne site,
link |
you will also get 20% off any of the other supplements
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that Thorne makes.
link |
We partnered with Thorne
link |
because they have the absolutely highest levels
link |
of stringency in terms of the quality and quantity
link |
of the supplements that they put in their formulations.
link |
And last but not least,
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I want to thank you for embarking on this journey
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of trying to understand what is depression,
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how does it work, and how to treat it.
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And thank you for your interest in science.
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I'll see you next time.