Remastered: Depression (with Dr. Gerard Sanacora)

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Hey there, Ashley here. I'm currently off gallivanting in Denver
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at podcast Movement, so I'm re releasing this very popular
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episode that dropped back in twenty twenty one. Chances are
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you've never heard it before, but even if you have,
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it's worth hearing again, not just because the stuff that
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doctor Santa Kora has to say is only getting more important,
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but also because it's fully remastered with fancy AI audio
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tools thanks to script, so it's a much better listen. Seriously,
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if you're curious, check out the original in the feed
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and then listen to this one. The difference is pretty dramatic.
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And if you're watching on YouTube, hi, I didn't record
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video for this back in the day, so you're going
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to get an audiogram. I made it as fancy as
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I could for you. Hope you'll like it. I'll be
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back at the end to see you off for now
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on with the show. I used to think that depression
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was easy to spot. I mean, I knew that people
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with depression were sad, and they'd start to skip their
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favorite activities to stay in bed all day. They'd basically
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just shut off from the world. But it turns out
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that depression is so much more complicated than that. Like,
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depression can make it hard to concentrate. You can be
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going to work every day like you always do, but
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you just start to forget things and make silly mistakes.
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Some people, particularly older people, they might even fall more
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frequently because they're not paying attention. Depression can make you angry.
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If you feel hopeless on the inside, you might lay
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the blame with others, and that can make you lash
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out at friends and family. And depression can hurt. Studies
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have shown that people with depression have a decreased tolerance
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for pain. Your head, your joints, your whole body might
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just feel worse overall. And just like there are a
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lot of different symptoms of depression, there are also a
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lot of different causes, causes that scientists haven't fully untangled.
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In fact, depression is still a pretty big mystery. We
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can't fully explain why it happens, what's going on in
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the brain when it does happen, or how exactly therapies
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and medications help. But one thing we do know is
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that they do help, and that our treatments for depression
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are getting better all the time, despite the fact that
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those treatments can come from some pretty strange places. Today,
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we're going to talk about what we do and don't
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know about depression, why not knowing is actually okay, and
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why hallucinogens are making their way into the clinic. I'm
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Ashley Hamer, and this is Taboo Science, the podcast that
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answers the questions you're not allowed to ask. Depression is
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incredibly common, scarily common, Like more than two hundred and
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sixty million people worldwide are affected by depression. So you'd
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think this would be an easy thing to answer. What
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is depression?
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That is actually a very good question.
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That's doctor Gerard Santa Kora. He's the director of the
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Yale Depression Research Program and co director of the Yale
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Interventional Psychiatry Service, And to him, the question isn't so
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much what depression is as what it isn't.
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Depression is an interesting thing. That is actually what we
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call a diagnosis of exclusion. So in medicine, that means
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that you have a set of symptoms signs and we
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can't find an explanation, so for depression, and it's typically
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a set of nine core symptoms related to sleet, appetite, mood, concentration,
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zest for life, willingness, to live relating to those general
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categories that affect your cognition, perception, emotions, and we can't
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find another explanation for it. So, in other words, we
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can't find an endochronological problem such as hypothyroidism, or we
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don't find another neurologic disorders such as parkinson as that.
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Could be related.
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According to the latest edition of the Diagnostic and Statistical
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Manual of Mental Disorders, or the DSM five, these are
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the things the symptoms can't be caused by in order
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for it to be categorized as depression. They can't be
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caused by a medication or drug abuse. They can't be
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caused by another medical condition, and they can't be linked
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with manic episodes or better explained by other psychotic disorders
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like schizophrenia. Until twenty thirteen, they also couldn't be explained
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by bereavement after the loss of a loved one, but
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the DSM five removed that as an exclusion. That's because
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grief doesn't exactly protect you from depression, and it can
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sometimes lead to it. Do we know what does cause it?
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Then? I think the.
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Big question is is it an it? Which you said,
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do what causes it? It's probably many different path of
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physiological pathways to get to what we call depression. And
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there's probably many different paths of physiologies actually chysical changes
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and bringing structured function that we call depression.
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So it's very.
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Unlikely that it's a single illness or a single disease.
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It's a disorder that probably is what we call heterogeneous,
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meaning there's many different ways you can get that diagnosis.
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Yeah, that strikes me as strange because you did just
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say that if it's something that we know isn't endocrine
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and it isn't like it isn't these things, but it
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sounds like it could be a lot of different things exactly.
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So we can tell you. That's why the diagnosis of
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exclusion is. We can tell you what it isn't, but
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we can't tell you what it is.
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There are a few risk factors we know can lead
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to depression, though stress at home or at work, a
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traumatic event, isolation, and other stressors can all have an effect.
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Chronic pain and other ongoing medical symptoms can lead to depression.
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And then, of course there are the biological factors. Your brain, chemistry,
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your genetics, and even your personality can all influence your
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risk of depression. So if depression can be caused by
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lots of different things, both in your life and in
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your brain, how do we fix it.
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For the past five or six decades, the primary types
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of treatment has been either talk therapy or antidepressant therapies
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for the most part. There are neuromodulatory therapies and other
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types of therapy that's used there too, but those are
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the predominant, especially as a first step in the treatment
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of depression.
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Right, And there are a lot of different types of antidepressants,
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I understand.
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So yes and no, there are a lot of different
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antidepressants or when we're talking about oral antidepressant medications, so
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there are a lot of individual, different ones that are
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well over two dozen approved antidepressants, but they do generally
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tend to fall in one of a few small categories.
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The monoaminergic medicine, So the ones that go back the
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furthest of the ones that we currently use, the monoamine
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oxidation inhibiting drugs or the tricyclic antidepressant drugs, those really
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target primarily neuropinephrine serotonin.
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That was a lot of big words, so let's back up.
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Monoaminergic medicines target monoamines, which is just an umbrella term
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for dopamine, serotonin, and norepinephrine. Those are the brain chemicals
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that are thought to be involved in depression, specifically when
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you've got low levels of them. It's the job of
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these chemicals to help brain cells communicate with one another,
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and when there isn't enough of them, those signals can't
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get through. So then monoamine oxidase inhibitor drugs block an
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enzyme called monoamine oxidase, which is responsible for coming in
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and cleaning up any leftover monoamines. Once they've done their
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job by blocking the enzyme, the drug is believed to
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keep levels of those feel good chemicals high. Tricyclic antidepressants
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to do something similar, just in a different way. They
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keep some of these chemicals, mostly norepinephrine, from being reabsorbed
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into nerve cells. Like doctor Santacorus said, these are the
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drugs that go back the farthest. They've also got a
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lot of side effects, so these days they're not the
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choice for someone who's new to antidepressants. We've got more
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options these days.
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And then the SSRIs that many people heard of that
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we developed later, the prozacs and others in that class
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are the selective serotonin reuptake and hignism.
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Selective serotonin reuptake inhibitors, or SSRIs inhibit the reuptake of serotonin,
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or to put it another way, they keep nerve cells
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from reabsorbing serotonin in order to maintain high levels in
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the brain. This sounds a little bit like those tricyclic antidepressants,
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but these are different. For one thing, tricyclics mostly work
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on norepinephrin and SSRIs mostly work on serotonin. And SSRIs
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are a lot more precise than tricyclic antidepressants. They're better
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at targeting the receptors that are important, rather than just
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hitting receptors all over the body and causing unpleasant side effects.
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Prozac is one kind of ssri.
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Most of those drugs, and even many of the versions
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that are followed after that, really are drugs that either
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target ner epinephrinurse or at one and that is the
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large majority of the medications out there. There are a
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few other smaller classes that are beginning to develop that
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actually are targeting different neurotransmitter systems and different mechanisms of action.
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So do these drugs work?
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This is a little bit of a loaded question, because
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in fact they are quite effective. The medicines do tend
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to work very well. The struggle is that placebo also
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works fairly well too, in the treatment of depression, and
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it works fairly well in the treatment of a lot
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of different disorders, even outside of psychiatry. So I personally
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don't like the term placebo because I think at this
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point it is laden with a connotation of sort of
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shouldn't have an effect. It's sort of a trick or
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something where you know, giving that shouldn't have benefit. I
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think the term that is more appropriately used as a
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non specific effect. So we know that, for example, a diet,
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if you sawt somebody on a diet, besides the diet,
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they start to pay a lot more attention to what
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they're eating, they start to increase exercise, they start.
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To do a lot of other things.
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That is, in addition, it's non specific to the type
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of diet that you give. And it's very much like
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that with medications or any treatment. Once you start to
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get involved in the treatment, it's not just the pill
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you're taking, and even the pill itself has years of conditioning.
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So we learned that if we take a pill or
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headache goes away. So the next time we have a headache,
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even this the simple act of taking anything, we're conditioned
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to have that belief that our headache is going to work.
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So you become conditioned to certain things are going to work.
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So that's part of a placebole response, But there are
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many other parts of that placebo response that have big effects,
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like you start to pay more attention to your emotions,
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you start to think about things differently, and you start
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to see a therapist or a doctor, so somebody else
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that is now you can share your concerns and thoughts
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to it. So it's a lot more involved in taking
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a medicine or any fulm medical treatment than the simple
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specific effect of the drug or the surgery or whatever
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you're getting it. So it's all those non specific effects
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and they are incredibly palatful. The medicines work quite well
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if you would just look at people that took medicine
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and people that didn't take medicine. But it's called a
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wait less type approach where you look at people that
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started on treatment people that don't. Where it becomes more
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difficult to reliably show a difference is when you have
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a treatment used against the placebo because the non specific
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attacks are so large, you need large sample sizes to
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really show how much benefit the drug has over the
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non specific effects. The danger is that I really do
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try to make clear, is that you don't get the
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nonspecific effects unless you take the drug in many care,
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or unless you take the treatment, whether it's a drug,
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whether it's a talk therapy, whether it's whatever. You can't
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really extract one from the other so clearly, And that's
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where things get very complicated.
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Got it. So when someone just sees the headline that
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antide presents work about the same as placebo, there's a
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lot more going on there. It's much more complicated than
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you just think, like, oh, that just means it doesn't work.
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Like that's not what it means.
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Exactly, And that's where the there's a miscommunication or it
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could be misleading. And it's very important. And I don't
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think too many people spend nearly as much time as
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I do and others looking at this issue. So if
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you just hear that, I think it's a natural response
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to say, oh, well, if it doesn't work much better placebo,
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then it doesn't work very well.
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But that's not really what it.
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Means, but it does seem like with some drugs, I
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don't know, for heart conditions, it's like you give the
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drug and most people have about the same reaction. Maybe
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I'm oversimplifying, but I.
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Think you're oversimplifying much more than you think you are.
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Really well, yeah, I mean, I guess that's like the perception, right, yeah.
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And I think that's a misperception. There are relatively high
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placebo response rates for anti hypertensors. They're relatively high sham
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response rates to surgeries like orthopedic surgeries. The non specific
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effects go well beyond what we typically think of in depression.
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Even things like Parkinson's disease, which you wouldn't imagine would
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have big nonspecific effects as notorious or very large placebo effects.
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Doctor Santa Korus says that even the experience some people
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have with antidepressants where they need to try many different
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kinds before they find one that works for them, that's
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pretty similar to hypertension medications. People usually start on, say
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a diuretic that doesn't work, They'll try a beta blocker,
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and on and on.
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It's very common, especially in the treatment of hyperrotections. It
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is a good example of that. So the trumant of
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depression isn't so unique in that way.
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But antidepressants like these aren't the only options out there. Recently,
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research has demonstrated real promise for some drugs that I,
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for one, was told to stay away from in their class.
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You study a bunch of different therapies for depression, and
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one of those is ketamine. Like when I first heard
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that people were using ketamine to treat depression, I was like,
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how could that possibly work? Like that's like a street drug, right,
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how does that work?
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So ketamine was originally an anesthetic agent. It was a
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major breakthrough in the field of anesthesia, and you have
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to approve in nineteen.
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Seven, as you said, it's an anesthetic. It really gained
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a lot of prominence because it's.
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A relatively safe aesthetic that could be used in situations
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where you weren't able to monitor patients as closely, so
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in chill pass orles. It became very popu in third
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world countries. It's still a critical drug as the use
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of an anesthetic, and it's even in the US. It's
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use commonly in pediatric anesthesia or emergency rooms where you
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need a quick use of an anesthetic.
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If you're wondering why someone would use an anesthetic illegally, well,
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it's because ketamine works by putting people in a dissociative
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state that detaches them from any pain. You can see
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how that might be desirable outside of the operating room.
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And that's before you get to its hallucinogenic effects.
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Again, the lay person may look at this as kind
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of a street drug, but it has a fifteen year
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history of being considered a critical drug to the world
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by the World Health Organization. So this is a long
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medical history, but it still is a pretty unique story
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that this anesthetic drug would have antidepressing effects.
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Yeah, and so how why does it have antidepress and effects?
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So I would I could to do exactly why.
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I can tell you why we think it does, and
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I can tell you why it was initially testing.
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There was increasing evidence, really towards.
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The end of the last millennium, in the nineteen nineties
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or so, that the neurobiology of depression was much more
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involved than that idea of the chemical imbalance or that
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there was low serotonin, low Europe and effort levels, which
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is really where the thinking was in the nineteen eighties
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and nineties, and we started to realize that the brain
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was much more complex and there was many other neurotransmitter
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systems that were involved, and also that the plasticity of
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the brain, the way the brain can actually change and
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adapt to different environments and.
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Different evensfe was very important.
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And they became increasing evidence that parts of the brain
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that were predominantly using glutamate, which is the major neurotransmitter
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in the brain. So about eighty percent of all your neurons,
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the cells in your brain use glutamate as its primary communication.
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You know, it's primary or a transmitter. So it began
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increasing that glutimate and gabba, which is a major in emiture.
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That those two charatrisms probably have pots to do with
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the path of the physiology of depression. As we said,
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whatever depression is that broader sense of and the ability
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to modulate plasticity.
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One thing we've learned is that stress and trauma can
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actually change the structure of the brain. Animal studies have
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found that chronic stress can degrade neurons and parts of
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the brain responsible for learning, memory, and executive function. Those
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areas are also smaller with fewer connections in patients with depression.
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Some of that is probably because of problems with the
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neurons that deal with glutamate and GABBA.
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So is at that time some of my colleagues had, Yeah,
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John Crystal Brobern and others had the idea that ketamine
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being a drug that specifically targets the glutamate system what's
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called the NMBA receptor which binds to glutamate.
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The fact that they knew that there was this.
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Drug out there that had been used safely for decades
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had a dramatic effect on this neurotransmitter system. They really
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followed a pretty simple apothesis that just may have an
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effect on people with depression, and that was the original
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study done in the late nineteen nineties published in two
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thousand that shows this very rapid on set of effect,
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which really was a surprise to everybody. I mean, everybody
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was interested in it, but I don't think anybody in
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New tact I'm sure none of those primary office, because
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they make it very clear thought that they would see
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this rapid improvement within hours that would be sustained for
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at least days following a treatment.
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Wow.
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But because it's an anesthetic, does it I mean, does
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it make it so you have you can't do everyday
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activities when you're using it.
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So that's the other extremely interest in resting an important
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point to make with ketemine, especially the early studies with ketymine.
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So it's not giving at the level that you would
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use for anesthesia, but it is still given at a
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level that would dramatically impair your cognition. So you at
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the dose that is being used original studies, yes, you
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do need to be monitored closely and you're not going
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to be going about your normal daily activities. But unlike
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most other antidepressants where you have to take it all
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the time, this was something that you take and typically
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an infusion originally was lasting for about forty minutes and
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then you stop it. Ketymine is metabolized very quick thing
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about it, so it disappears out of your system pretty rapidly.
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But then the antidepressant effect actually build over time after
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you stop it, so the majority of the large majority
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of that time you're not on the drought that you
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actually get to benefit, which is again a novel approach
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and really a completely new finding within the field.
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So is this becoming more widespread? Are more people using
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this in just like therapy settings.
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So it is growing dramatically in twenty nineteen, the FDA
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has approved a version of kenemine, which is actually esketemine,
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which is really just half of the natural substance that
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carves in what we were seen a ketemine. It's just
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half of what we would normally find in regular academy.
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It was approved for the treatment of patients with treatment
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resistant depression, and then more recently in twenty twenty, was
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actually approved for patients with depression who also have suicidal ideations.
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Even though it wasn't FDA approved until twenty nineteen, clinics
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had been using ketamine to treat depression since twenty twelve,
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and that wasn't illegal. Instead, it was just yet another
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benefit of a drug that had been used for something
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else for decades. See these clinics just used ketamine off label,
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the way doctors commonly prescribe an anti seizure medication for
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bipolar disorder, or how some musicians I know get beta blockers,
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a type of blood pressure medication for stage fright. It's
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a thing. Using drugs off label is legal. It just
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carries some extra risks since the FDA hasn't determined that
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the drug is safe and effective for that off label use.
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But that was then, so it is now n FDA
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approved indicated medicine for depression, but it's not a medicine
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for everybody, definitely, and it is still a medicine that
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requires relative and close monitoring, especially in the way that
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it is being given as of today and according to
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the SDA.
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Regulations and guidance.
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We talked a lot about kidamine as a game changer,
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which I really think it was because we were locked
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into about fifteen years of thinking very specifically about how
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to treat depression and either would talk therapies or with
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oral antipress medications that primarily targeted serotomin Europe and efferent.
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I mean, there was always the treatments like.
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ECT that actually predate electro convulsive therapy, that predate even
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the oral medications. But since that time of ketamine, there's
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really been an explosion of alternatives treatments. Besides the regular
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oral antidepressants and talk therapies, there's neurostimulatory therapies like transcrinomagnetic
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stimulation that has really become quite popular. There's nerve simulation,
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there's even studies with deep brain stimulation that are going on.
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But then in terms of other pharmacologic treatments. There are
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several new lines of interest, but the one that I
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think recently has gained a lot of attention and it
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is extremely interesting to many people, is the idea of
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using drugs such as psilocybin, drugs that fall into this
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general psychedelic category of drugs.
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00:25:06.200 --> 00:25:09.680
Yep Ketamine isn't the only dark horse in this race.
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There's also psilocybin, the active ingredient in what some call
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magic mushrooms. Yeah, how does psilocybin help with depression? Do
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we know that?
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So?
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First of all, I don't think we can say we
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know that it does help with depression.
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It we're still doing those studies. So there are early
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reports that.
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Look very promising, but I always do emphasize these are
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early reports and we really still have to demonstrate that
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this isn't effective treatment and depression, and that really is
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the first step, and that I think many of us
409
00:25:45.960 --> 00:25:52.200
are working very hard to determine what the actual efficacy
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and obviously the safety of this treatment would be true depression.
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In terms of if it does work, how it works,
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there are many different hypotheses. I think sort of the
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mainstreamline of thinking about it is that it may work
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very similar to ketamine. So we think what ketamine, we do,
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and quite possibly these psychedelic medications I mentioned before, this
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idea of neuroplasticity actually altering the way the brain cells
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communicate with each other, and actually even structurally altering the
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00:26:22.279 --> 00:26:24.880
way the brain cells communicate with each other and how
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00:26:24.880 --> 00:26:29.039
they adapt to novel environments and novel events. And it
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looks like just as ketamine can have these rapid effects
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on the neuron's ability to communicate with each other, it
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looks like some of these psychedelic type methicines like psilocybin,
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may have very similar effects. Now, obviously these are still
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hypotheses that need to be tested, and there are other hypotheses.
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These may have.
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More more effects that go well beyond the simple brain
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chemistry or even the neuroplasticity, in terms of some of
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the spiritual side of these drugs and the other they
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00:27:00.440 --> 00:27:05.039
may have in social relatedness. So there are many different hypotheses,
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00:27:05.079 --> 00:27:07.960
so we really don't know how any of them work
431
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for sure, but we are starting to learn.
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Quite a bit.
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00:27:10.759 --> 00:27:14.039
Yeah, one thing I've heard is that an idea might
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00:27:14.079 --> 00:27:17.720
be that it gives you more of a sense of
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oneness with the world and takes you out of your
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own like focusing in on your own self. And because
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depression is there's a lot of like looking inward that
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it helps that way.
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00:27:28.720 --> 00:27:31.359
So that is definitely one of the hypotheses that have
440
00:27:31.480 --> 00:27:35.599
been proposed, and there's a fair amount of research looking
441
00:27:35.640 --> 00:27:38.640
into that. I don't think any of these mechanisms are
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00:27:38.799 --> 00:27:42.079
necessarily exclusive. I think the likelihood is that there's some
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component of all of these in generating the bashits that
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are seen.
445
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But I do say, yeah, the first.
446
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Part is we'd have to demonstrate to a high degree
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of certainty that these are effective and safe treatments.
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We're still at that stage.
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So here's what I didn't realize about depression. Just because
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we don't fully understand how it works in the brain
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doesn't mean we can't find better ways to give people relief.
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You don't have to know how something works to know
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that it does work. Millions of people suffer from depression,
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and researchers like doctor Santa Kora are constantly making progress
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toward more effective treatments and maybe someday we'll know how
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they work. So well, thanks for listening. I'm back in
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twenty twenty three to read the credits. Thanks a ton
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to Girard Santa Kora for talking to me back in
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twenty twenty one. He's since done a lot more work
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on ketamine's role in treating depression, and all include links
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00:28:47.359 --> 00:28:49.640
to some of that work in the citations on the website.
462
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And if you'd like to hear a really excellent podcast
463
00:28:52.279 --> 00:28:56.039
episode all about ketamine which also features doctor Santa Kora,
464
00:28:56.240 --> 00:28:59.240
definitely check out the Science Versus episode about it from
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00:28:59.279 --> 00:29:01.480
April of this year. All include a link in the
466
00:29:01.519 --> 00:29:04.759
show notes. Taboo Science is written and produced by me
467
00:29:04.920 --> 00:29:08.519
Ashley Hamer. The theme was by Danny Lapotka of DLC Music.
468
00:29:08.839 --> 00:29:12.160
Episode music is from Epidemic Sound. If you need music
469
00:29:12.160 --> 00:29:14.400
for a project, just use my referral link in the
470
00:29:14.400 --> 00:29:17.480
show notes and it'll help out the show. We've got
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00:29:17.519 --> 00:29:20.640
some really fascinating new topics coming in the next couple months.
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00:29:20.759 --> 00:29:24.000
I for one am really excited, so hit that subscribe
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00:29:24.039 --> 00:29:26.359
button to make sure you don't miss an episode and
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tune in next time. I won't tell anyone