Remastered: Depression (with Dr. Gerard Sanacora)

How much do we really know about depression? In this remastered episode, Gerard Sanacora, director of the Yale Depression Research Program and Co-director of the Yale Interventional Psychiatry Service, reveals that even doctors don’t fully get the biological roots behind depression’s mix of mental and physical woes. But that doesn’t mean we don’t have effective treatments — and those treatments are only getting better. For example, ketamine and psilocybin are being studied as unconventional treatments to reshape depressed brains. Tune in to learn how medicine moves forward in understanding this serious condition, even when the science isn’t clear.

New research from Dr. Sanacora:

Citations and further reading:


Ashley: Hey there, Ashley here. I’m currently off Gallivanting in Denver at Podcast Movement, so I’m re-releasing this very popular episode that dropped back in 2021. Chances are, you’ve never heard it before, but even if you have, it’s worth hearing again, not just because the stuff that Dr. Sanacora has to say is only getting more important, but also because it’s fully remastered with fancy AI audio tools — thanks Descript! — so it’s a much better listen. Seriously, if you’re curious, check out the original in the feed and then listen to this one. The difference is pretty dramatic. And if you’re watching on YouTube, hi! I didn’t record video for this back in the day, so you’re gonna get an audiogram. I made it as fancy as I could for you. Hope you like it.

Ashley: I’ll be back at the end to see you off. For now on with the show.

Ashley: I used to think that depression was easy to spot. I mean, I knew that people with depression were sad and they’d start to skip their favorite activities to stay in bed all day. They’d basically just shut off from the world. But it turns out that depression is so much more complicated than that.

Ashley: Like, depression can make it hard to concentrate. You can be going to work every day like you always do, but you just start to forget things and make silly mistakes. Some people, particularly older people, they might even fall more frequently because they’re not paying attention. Depression can make you angry. If you feel hopeless on the inside, you might lay the blame with others and that can make you lash out at friends and family.

Ashley: And depression can hurt. Studies have shown that people with depression have a decreased tolerance for pain. Your head, your joints, and your whole body might just feel worse overall. And just like there are a lot of different symptoms of depression, there are also a lot of different causes, causes that scientists haven’t fully untangled.

Ashley: In fact, depression is still a pretty big mystery. We can’t fully explain why it happens, what’s going on in the brain when it does happen, or how exactly therapies and medications help. But one thing we do know is that they do help and that our treatments for depression are getting better all the time, despite the fact that those treatments can come from some pretty strange places.

Ashley: Today we’re gonna talk about what we do and don’t know about depression, why not knowing is actually okay, and why hallucinogens are making their way into the clinic. I’m Ashley Hamer, and this is Taboo Science. The podcast that answers the questions you’re not allowed to ask.

Ashley: Depression is incredibly common. Scarily common. Like more than 260 million people worldwide are affected by depression. So you’d think this would be an easy thing to answer. What is depression?

Gerard Sanacora: That is actually a very good question.

Ashley: That’s Dr. Gerard Sanacora. He’s the director of the Yale Depression Research Program and co-director of the Yale Interventional Psychiatry Service.

Ashley: And to him, the question isn’t so much what depression is as what it isn’t.

Gerard Sanacora: Depression is an interesting thing that is actually what we call a diagnosis of exclusion. So in medicine that means that you have a set of symptoms, signs, and we can’t find an explanation. So for depression, it’s typically a set of nine core symptoms related to sleep, appetite, mood, concentration, zest for life, willingness to to live related to those general categories that affect your cognition, perception, emotions, and we can’t find another explanation for it.

Gerard Sanacora: So in other words, we can’t find an endocrinological problem such as hypothyroidism, or we don’t find another neurologic disorder such as Parkinsonism, that could be related.

Ashley: According to the latest edition of the Diagnostic and Statistical Manual of Mental Disorders, or the DSM V, these are the things the symptoms can’t be caused by in order for it to be categorized as depression:

Ashley: They can’t be caused by a medication or drug abuse. They can’t be caused by another medical condition, and they can’t be linked with manic episodes or better explained by other psychotic disorders like schizophrenia. Up until 2013, they also couldn’t be explained by bereavement after the loss of a loved one. But the DSM V removed that as an exclusion. That’s because grief doesn’t exactly protect you from depression, and it can sometimes lead to it.

Ashley: Do we know what does cause it, then?

Gerard Sanacora: I think the big question is, is it an it? Which you said did what causes it. It’s probably many different pathophysiological pathways to get to what we call depression.

Gerard Sanacora: There’s probably many different pathophysiologies, actually, physical changes in brain structure function that we call depression. So it’s very unlikely that it’s a single illness or a single disease. It’s, it’s a disorder that probably is what we call heterogeneous, meaning there’s many different ways you can get that diagnosis.

Ashley: Yeah, that, that strikes me as strange because you did just say that if it’s something that we know isn’t endocrine and it isn’t like it isn’t these other things, but it sounds like it could be a lot of different things.

Gerard Sanacora: Exactly. So we can tell you — that’s what a diagnosis of exclusion is — we can tell you what it isn’t, but we can’t tell you what it’s,

Ashley: There are a few risk factors we know can lead to depression, though.

Ashley: Stress at home or at work, a traumatic event, isolation, and other stressors can all have an effect. Chronic pain and other ongoing medical symptoms can lead to depression. And then of course, there are the biological factors. Your brain chemistry, your genetics, and even your personality can all influence your risk of depression.

Ashley: So if depression can be caused by lots of different things, both in your life and in your brain, how do we fix it?

Gerard Sanacora: For the past five or six decades, the primary types of treatment has been either talk therapy or antidepressant therapies, for the most part. There are neuromodulatory therapies and other types of the that’s used there too, but those are the predominant, especially as a first step in the treatment of depression.

Ashley: Right. And there are a lot of different types of antidepressants, I understand.

Gerard Sanacora: So, yes and no. There are a lot of different antidepressant or, you know, we’re talking about oral antidepressant medications. So there are a lot of individual different ones. There are well over two dozen approved antidepressants, but they do generally tend to fall in one of a few small categories.

Gerard Sanacora: The monoaminergic medicines are the ones that go back the furthest, uh, of the ones that we currently use. The monoamine oxidase inhibiting drugs. Or the tricyclic antidepressant drugs. Those really target primarily norepinephrine, serotonin.

Ashley: That was a lot of big words. So let’s back up. Monoaminergic medicines target monoamines, which is just an umbrella term for dopamine, serotonin, and norepinephrine. Those are the brain chemicals that are thought to be involved in depression, specifically when you’ve got low levels of them. It’s the job of these chemicals to help brain cells communicate with one another, and when there isn’t enough of them, those signals can’t get through.

Ashley: So then monoamine oxidase inhibitor drugs block an enzyme called monoamine oxidase, which is responsible for coming in and cleaning up any leftover monoamines once they’ve done their job. By blocking the enzyme, the drug is believed to keep levels of those feel-good chemicals high.

Ashley: Tricyclic antidepressants do something similar just in a different way. They keep some of these chemicals, mostly norepinephrine, from being reabsorbed into nerve cells. Like Dr. Sanacora said, these are the drugs that go back the farthest. They’ve also got a lot of side effects. So these days, they’re not the first choice for someone who’s new to antidepressants. We’ve got more options these days.

Gerard Sanacora: And then the SSRIs that many people heard of that were developed later, the Prozacs and others in that class, uh, are the selective serotonin reuptake inhibitors.

Ashley: Selective serotonin re-uptake inhibitors or SSRIs inhibit the re-uptake of serotonin. Or to put it another way, they keep nerve cells from reabsorbing serotonin in order to maintain high levels in the brain.

Ashley: This sounds a little bit like those tricyclic antidepressants, but these are different. For one thing, tricyclics mostly work on norepinephrine and SSRIs mostly work on serotonin. And SSRIs are a lot more precise than tricyclic antidepressants. They’re better at targeting the receptors that are important rather than just hitting receptors all over the body and causing unpleasant side effects.

Ashley: Prozac is one kind of SSRI.

Gerard Sanacora: So most of those drugs and even many of the versions that have followed after that really are drugs that either target norepinephrine or serotonin. Uh, and that is the large majority of the medications out there. There are a few other smaller classes that are beginning to develop that actually are targeting different neurotransmitter systems and different mechanisms of action.

Ashley: So do these drugs work?

Gerard Sanacora: This is a a little bit of a loaded question ’cause in fact they are quite effective. The medicines do tend to work very well. The struggle is that placebo also works fairly well too in the treatment of depression. And it works fairly well in the treatment of a lot of different disorders, even outside of psychiatry.

Gerard Sanacora: So I personally don’t like the term placebo. Because I think at this point it is laden with a connotation of sort of, it shouldn’t have an effect. It, it’s sort of a trick or something we’re, you know, giving that shouldn’t have, have benefit. I think the term that is more appropriately used is a non-specific effect.

Gerard Sanacora: So we know that, for example, a diet, if you start somebody on a diet besides the diet, they start to pay a lot more attention to what they’re eating. They start to increase exercise, they start to do a lot of other things that is in addition. It’s non-specific to the type of diet that you give. It’s very much like that with medications or, or any treatment.

Gerard Sanacora: Once you start to get involved in the treatment, it’s not just the pill you’re taking and, and even the pill itself has years of conditioning. So we learn that if we take a pill, our headache goes away. So the next time we have a headache, even just the simple act of seeking anything, we’re conditioned to have that belief that our headache is gonna go away. So you become conditioned to certain things are gonna work.

Gerard Sanacora: So that’s part of a placebo response, but there are many other parts of that placebo response that have big effects. Like you start to pay more attention to your emotions. You start to think about things differently, and you start to see a therapist or a doctor, so somebody else that is now you can share your concerns and thoughts with.

Gerard Sanacora: So it’s a lot more involved than taking a medicine or or any form of medical treatment than the simple, specific effect of the drug or the surgery or whatever you’re getting it. So it’s all those non-specific effects and they’re incredibly powerful.

Gerard Sanacora: The medicines work quite well if you would just look at people that took medicine and people that didn’t take medicine, but. It’s called a wait list type approach where you look at people that started on treatment, people that don’t. Where it becomes more difficult to reliably show a difference is when you have a treatment used against the placebo. Because the non-specific effects are so large, you need large sample sizes to really show how much benefit the drug has over the non-specific effects.

Gerard Sanacora: The danger is, I, I really do try to make clear, is that you don’t get the non-specific effects unless you take the drug in many cases, or unless you take the treatment. Whether it’s a drug, whether it’s a talk therapy, whether it’s whatever. You can’t really extract one from the other so clearly, and that, that’s where things get very complicated.

Ashley: Got it. So when someone just sees the headline that, antidepressants work about the same as placebo, there’s a lot more going on there. It’s much more complicated than you just think like, oh, that just means it doesn’t work. Like that’s not what it means.

Gerard Sanacora: Exactly. And that’s where the, there’s a miscommunication or, or it could be misleading. And it, it’s very important and, and I don’t think too many people spend nearly as much time as I do and others looking at this issue. So if you just hear that, I think it’s a natural response to say, oh, well if it doesn’t work much better than placebo, then it doesn’t work very well. But that’s not really what it means.

Ashley: But it does seem like with some drugs, I don’t know, for heart conditions, it’s like you give the drug and most people have about the same reaction. Maybe. Maybe I’m oversimplifying, but —

Gerard Sanacora: I think you’re oversimplifying much more than you think you are.

Ashley: Really. Well, yeah. I mean, I guess that’s like the perception, right?

Gerard Sanacora: Yeah. And, and I think that’s a, a misperception. There are relatively high placebo response rates for antihypertensives. There, there are relatively high sham response rates to surgeries like, uh, orthopedic surgeries. The non-specific effects go well beyond what we typically think of in depression. Even things like Parkinson’s disease, which you wouldn’t imagine would have big non-specific effects is notorious for very large placebo effects.

Ashley: Dr. Sanacora says that even the experience some people have with antidepressants where they need to try many different kinds before they find one that works for them. That’s pretty similar to hypertension medications. People usually start on say, a diuretic, and if that doesn’t work, they’ll try a beta blocker and on and on.

Gerard Sanacora: It’s very common, especially in the treatment of hypertension is a good example of that. So the treatment of depression isn’t so unique in that way.

Ashley: But antidepressants like these aren’t the only options out there. Recently, research has demonstrated real promise for some drugs that I, for one, was told to stay away from in DARE class.

Ashley: You study a bunch of different therapies for depression, and one of those is ketamine. Like when I first heard that people were using ketamine to treat depression, I was like, how could that possibly work? Like, that’s like a street drug, right? How does that work?

Gerard Sanacora: So ketamine was originally an anesthetic agent. It was, uh, a major breakthrough in the field of anesthesia. It was actually FDA approved in 1970, for, as the use of anesthetic. It really gained a lot of prominence ’cause it’s a relatively safe anesthetic that could be used in situations where you weren’t able to monitor patients as closely.

Gerard Sanacora: So in field hospitals, it became very popular in third world countries, it’s still a critical drug as the use of an anesthetic. And it’s, even in the US, it’s used commonly in pediatric anesthesia or emergency rooms where you need a quick, uh, use of an anesthetic.

Gerard Sanacora: If you’re wondering why someone would use an anesthetic illegally, well, it’s because ketamine works by putting people in a dissociative state that detaches them from any pain. You can see how that might be desirable outside of the operating room.

Gerard Sanacora: And that’s before you get to its hallucinogenic effects.

Gerard Sanacora: Again, the lay person may look at this as kind of a street drug, but it has a 50 year history of being considered a critical drug to the world by the World Health Organization. So this is a long medical history, but it still is a pretty unique story that this anesthetic drug would have antidepressant effects.

Ashley: Yeah. And so how, why does it have antidepressant effects?

Gerard Sanacora: So, I, I wish I could tell you exactly why. I can tell you what we, why we think it does. And I can tell you why it was initially tested.

Gerard Sanacora: There was increasing evidence really towards the end of the last millennium, in the 1990s or so, that the neurobiology of depression was much more involved than that idea of a chemical imbalance, or that there was low serotonin, low norepinephrine levels, which is really where the thinking was in the 1980s, 1990s.

Gerard Sanacora: And we started to realize that the brain was much more complex and there was many other neurotransmitter systems that were involved and also that the plasticity of the brain, the way the brain connects to change and adapt to different environments and different, uh, events in life was very important.

Gerard Sanacora: And there became increasing evidence that parts of the brain that were predominantly using glutamate, which is the major neurotransmitter in the brain. So about 80% of all your neurons, the cells in your brain use glutamate as its primary communication, you know, its primary neurotransmitter. So it became increasing that glutamate and GABA, which is the major inhibitor of neurotransmitters, that those two neurotransmitters probably have lot to do with the pathophysiology of depression, as we said, whatever depression is that broader sense of, and the ability to modulate plasticity.

Ashley: One thing we’ve learned is that stress and trauma can actually change the structure of the brain. Animal studies have found that chronic stress can degrade neurons and parts of the brain responsible for learning, memory, and executive function. Those areas are also smaller with fewer connections in patients with depression.

Ashley: Some of that is probably because of problems with the neurons that deal with glutamate and GABA.

Gerard Sanacora: So it was at that time some of my colleagues had, the idea, uh, like, uh, John Krystal and John — Rob Berman and others had the idea that ketamine being a drug that specifically targets the glutamate system and what’s called the NMDA receptor, which binds to glutamate, the fact that they knew that there was this drug out there that had been used safely for decades had a dramatic effect on this neurotransmitter system. They really followed a pretty simple hypothesis that this may have an effect on people with depression. And that was original study done in the late 1990s, published in 2000, that showed this very rapid onset of effect, which really was a surprise to everybody.

Gerard Sanacora: I mean, everybody was interested in it, but I don’t think anybody, and in fact, I am sure none of those primary authors ’cause they, they make it very clear, thought that they would see this rapid improvement within hours that would be sustained for at least days following a treatment.

Ashley: Wow. But because it’s an anesthetic, does it, I mean, does it make it so you have, you can’t do everyday activities when you’re using it.

Gerard Sanacora: So that, that’s the other extremely interesting and important point to make with ketamine, especially the early studies with ketamine. So it’s not given at the level that you would use for anesthesia, but it is still given at a level that would dramatically impair your cognition. So you, you at the dose that is being used in those original studies, yes, you do need to be monitored closely and you’re not gonna be going about your normal daily activities. But unlike most other antidepressants where you have to take it all the time, this was something that you take, and typically an infusion originally was lasting for about 40 minutes and then you stop it.

Gerard Sanacora: Ketamine is metabolites very quickly in your body, so it disappears out of your system pretty rapidly, but then the antidepressant effect actually builds over time after you stop it. So the majority, the large majority of that time, you’re not on the drug, that you actually get the benefit. Which is again, a novel approach and really a completely new finding within the field.

Ashley: So is this becoming more widespread? Are, are, are more people using this in just like therapy settings?

Gerard Sanacora: So it is growing dramatically and in 2019, the FDA has approved a version of ketamine, which is actually esketamine, which is really just half of the natural substance that occurs in what we call racemic ketamine.

Gerard Sanacora: It’s, uh, just half of what we would normally find in, in regular ketamine. It was approved for the treatment of patients with treatment-resistant depression, and then more recently, uh, in 2020, was actually approved for patients with depression who also have suicidal ideations.

Ashley: Even though it wasn’t FDA approved until 2019, clinics had been using ketamine to treat depression since 2012. And that wasn’t illegal. Instead, it was just yet another benefit of a drug that had been used for something else for decades.

Ashley: See, these clinics just used ketamine off-label the way doctors commonly prescribe an anti-seizure medication for bipolar disorder or how some musicians I know get beta blockers, a type of blood pressure medication, for stage fright. It’s a thing.

Ashley: Using drugs off-label is legal. It just carries some extra risks since the FDA hasn’t determined that the drug is safe and effective for that off-label use. But that was then.

Gerard Sanacora: So it is now an FDA approved, indicated medicine for depression, but it’s not a medicine for everybody, definitely. And it is still a medicine that requires relatively close monitoring, especially in the way that it is being given. You know, as of today, and according to the FDA regulations and guidance.

Gerard Sanacora: We talked a lot about ketamine as a game changer, which I really think it was because we were locked into about 50 years of thinking very specifically about how to treat depression, and either with talk therapies or with oral antidepressant medications that primarily targeted serotonin, norepinephrine.

Gerard Sanacora: I mean, there was always the treatments like ECT that actually predate, electroconvulsive therapy, that predate even the, the oral medications. Um, but since that time of ketamine, there’s really been an explosion of alternative treatments besides the regular oral antidepressants and, uh, chalk therapies.

Gerard Sanacora: There’s neuro stimulatory therapies like transcranial magnetic stimulation that has really, uh, become quite popular. There’s, uh, vagal nerve simulation. There’s even studies with deep brain stimulation that, that are going on. But then in terms of other pharmacologic treatments, there are several new lines of interest, but the one that I think recently has gained a lot of attention and is extremely interesting to many people is the idea of using drugs, uh, such as psilocybin. Drugs that fall into this general psychedelic category of drugs.

Ashley: Yep. Ketamine isn’t the only dark horse in this race. There’s also psilocybin, the active ingredient in what some call magic mushrooms.

Ashley: Yeah. How does psilocybin help with depression? Do we know that?

Gerard Sanacora: So, first of all, we, I don’t think we can say we know that it does help with depression, yet. We’re still doing those studies. So there are early reports that look very promising, but I always do emphasize these are early reports and you know, we, we really still have to demonstrate that this is an effective treatment in depression, and that really is the first step. And, and that I think many of us are working, um, very hard to, to determine, uh, what the actual efficacy and obviously the safety of this treatment would be for depression.

Gerard Sanacora: In terms of if it does work, how it works, there are many different hypotheses. Uh, I, I think sort of the mainstream line of thinking about it is that it may work very similar to ketamine. So we think what ketamine would do, and quite possibly these psychedelic medications I mentioned before, this idea of neuroplasticity actually altering the way the brain cells communicate with each other, uh, and actually even structurally altering the way that brain cells communicate with each other and how they adapt to novel environments and novel events.

Gerard Sanacora: And it looks like, just as ketamine can have these rapid effects on the neurons’ ability to communicate with each other, it looks like some of these psychedelic type medicines like psilocybin may have very similar effects. Now, obviously, these are still hypotheses that need to be tested, and there are other hypotheses.

Gerard Sanacora: These may have more, more effects that go well beyond the simple brain chemistry or even the neuroplasticity, uh, in terms of some of the spiritual side of, uh, these drugs and the other effects they may have in social relatedness. So there, there are many different hypotheses. So we really don’t know how any of them work for sure.

Gerard Sanacora: But we are starting to learn quite a bit.

Ashley: Yeah. One thing I’ve heard is that an idea might be that it gives you more of a sense of oneness with the world and takes you out of your own, like focusing in on your own self. And because depression is, there’s a lot of like looking inward that it helps that way.

Gerard Sanacora: So that is definitely one of the hypotheses that have been proposed. And there’s a fair amount of research looking into that. I don’t think any of these mechanisms are necessarily exclusive. I think the likelihood is that there’s some component of all of these in generating the benefits that are seen.

Gerard Sanacora: But I do say, yeah, the first part is we’d have to demonstrate to a high degree of certainty that these are effective and safe treatments. We’re still at that stage, so.

Ashley: Here’s what I didn’t realize about depression. Just because we don’t fully understand how it works in the brain doesn’t mean we can’t find better ways to give people relief.

Ashley: You don’t have to know how something works to know that it does work. Millions of people suffer from depression. And researchers like Dr. Sanacora are constantly making progress toward more effective treatments, and maybe someday we’ll know how they work so well.

Ashley: Thanks for listening. I’m back in 2023 to read the credits. Thanks a ton to Gerard Kora for talking to me back in 2021. He’s since done a lot more work on Ketamine’s role in treating depression, and I’ll include links to some of that work in the citations on the website.

Ashley: And if you’d like to hear a really excellent podcast episode all about ketamine, which also features Dr. Sanacora, definitely check out the science versus episode about it from April of this year.

Ashley: All include a link in the show notes. Taboo Science is written and produced by me, Ashley Hamer. The theme was by Danny Lopatka of D L C Music. Episode music is from Epidemic Sound. If you need music for a project, just use my referral link in the show notes and it’ll help out the show.

Ashley: We’ve got some really fascinating new topics coming in the next couple months. I, for one, am really excited. So hit that subscribe button to make sure you don’t miss an episode. And tune in next time. I won’t tell anyone.