For decades, the best drug therapies for treating depression, like SSRIs, have been based on the idea that depressed brains don’t have enough of the neurotransmitter serotonin. Yet for almost as long, it’s been clear that simplistic theory is wrong. Recent research into the true causes of depression is finding clues in other neurotransmitters and the realization that the brain is much more adaptable than scientists once imagined. Treatments for depression are being reinvented by drugs like ketamine that can help regrow synapses, which can in turn restore the right brain chemistry and improve whole body health.

In this episode, John Krystal, a neuropharmacologist at the Yale School of Medicine, shares the new findings in mental health research that are revolutionizing psychiatric medication.

Listen on Apple Podcasts, Spotify,  TuneIn or your favorite podcasting app, or you can stream it from Quanta.

Transcript

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STEVEN STROGATZ: According to the World Health Organization, 280 million people worldwide suffer from depression. For decades, people with chronic depression have been told their problem lies with a chemical imbalance in the brain, specifically a deficit in a neurotransmitter called serotonin. And based on this theory, many have been prescribed antidepressants known as selective serotonin reuptake inhibitors, or SSRIs, to correct this chemical imbalance.

This theory has become the common narrative, yet almost from the beginning, researchers have questioned the role of serotonin in depression, even though SSRIs do seem to bring a lot of relief to many people.

So, if bad brain chemistry isn’t at the root of chronic depression, what is? If the thinking behind SSRIs is wrong, why do they seem to help? And is it possible that as we get closer to the true cause of depression, we may find better treatments for other conditions as well?

I’m Steve Strogatz, and this is “The Joy of Why,” a podcast from Quanta Magazine, where my co-host Janna Levin and I take turns exploring some of the biggest mysteries in math and science today.

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Depression has touched my friends and colleagues, as I’m sure it has for many of you out there listening. So, I’m looking forward to learning more about the myths, the causes and treatments of depression this Mental Health Awareness Month with neuropharmacologist John Krystal.

John is the chair of the Yale Department of Psychiatry and a professor at the Yale School of Medicine. He’s also the co-director of the Yale Center for Clinical Investigation and the co-founder of Freedom Biosciences, which develops psychedelic therapeutics for mental health disorders. He’s a leading expert in the neurobiology of alcoholism, post-traumatic stress disorder, schizophrenia and depression, and perhaps best known for his research into ketamine as a treatment for depression.

John, thanks so much for joining us today.

JOHN KRYSTAL: Steve, great to be here.

STROGATZ: I would love to get into some of the research you’re doing, and we will, but I thought maybe as a starter we could get into some of the backstory about this chemical imbalance hypothesis for depression that I was mentioning in the introduction. What’s the basic premise of that theory and the debate surrounding it?

KRYSTAL: Sure. I think in your introduction you put it very well, which is that psychiatry has a history of discovering an effective treatment and working back from that treatment to a mechanism. And then assuming that that simple mechanism accounts for all that we understand about depression. In the case of antidepressant medications like SSRIs, their history actually goes back to 1957.

And in that year, a type of medication, a tricyclic antidepressant, was first found to be effective for treating symptoms of depression. And then in the 1960s, it was found that these drugs worked by blocking the uptake of two transmitters: one serotonin, the other norepinephrine. This chemical imbalance idea partly grew out of trying to find changes in levels of these chemicals in the brain.

People assumed that if a medication worked to treat depression by raising the brain level of serotonin and norepinephrine, that there must be some abnormality in these two systems in the brain and body that accounted for the effectiveness of the medications. And so they went hunting for them. And what often happens when you go hunting for something is that you find bits and pieces of clues, a kind of treasure map, that implicates serotonin and norepinephrine in some way in the biology of depression.

There are plenty of signs that the serotonin and norepinephrine system are somehow involved in the biology of depression, but not in the simple-minded way that people thought in the ’70s, say.

But it also grew out of the need for doctors who are prescribing these medications to try to explain to patients why they worked. Because when patients say, “Why do I need to take Prozac?” I suspect it was very awkward to say, “Oh, we really don’t know how Prozac works,” and “it just seems to work,” and “if you take it, then you’ll, you know — just trust me, it probably will help you.”

But that’s really, at some level, what they should have said at the time. Because the idea that depression was low serotonin was falsified by the fact that these drugs raised serotonin levels within an hour of taking the pill. In other words, they block the reuptake. But you don’t get better from your depression for usually weeks, if you’re fortunate enough to get better. And you don’t get to the peak level for often months after starting these medications.

And so it was really clear right from the beginning when these medications were being prescribed that depression was more complicated than just low serotonin or norepinephrine levels, and that these drugs worked by producing adaptations in the brain over time that accounted for their therapeutic effects. What those adaptations were, we’re still unfolding.

And so I would say, in response to what’s often asked, which is: If depression isn’t simply an abnormality in serotonin, why would you prescribe an SSRI? And I think the answer is that through serotonin and norepinephrine, we can promote the brain’s capacity for resilience against the adverse effects of stress and depression on the brain.

One of the great misconceptions about brain chemistry is that the brain is dominated by norepinephrine and serotonin. Together, norepinephrine and serotonin account for just a few percentage of the synapses in the brain. And the great majority, the great information highway of the brain, accounting for more than 90% of the synapses of the brain, are nerve cells that use a different chemical called glutamate to communicate.

STROGATZ: Hmm. Let me have you pause there for a second. When you speak about synapses as being, say, associated with serotonin or glutamate, let me just check that I’ve got this. So I’ve got nerve cells. They have fibers coming out of them, axons. At the end, there are synapses where nerve cells join to other nerve cells, right? There’s this connection. Now, I was a little bit surprised that you think of them as associated with one type of neurotransmitter. Is that right? That at a given synapse, it’s either going to dump out serotonin or glutamate? Should we think of it like that? One synapse, one neurotransmitter type?

KRYSTAL: Well, the story is more complicated than one neurotransmitter per nerve cell. That was the dogma, but it turns out that the brain is more complicated, but I will oversimplify to talk about the main neurotransmitter they release. The main neurotransmitter of these glutamate neurons is glutamate, serotonin, serotonin, GABA, GABA. So we’ll use that convention.

What’s really striking about the history of research on depression is that because some stress effects are mediated by norepinephrine and serotonin, and because the antidepressants worked by norepinephrine and serotonin — at least the initial antidepressants — we assumed that depression just involved these few percentage of the synapses in the brain.

And the more we learn about brain function, the more the main information highway of the brain, the glutamate system, and the main inhibitory tuning mechanism of the brain for glutamate… Glutamate is excitatory, and its effects are balanced by another chemical called GABA, which is the main inhibitory transmitter of the brain. And so the great balancing act within the brain is usually managed mostly by the interplay of GABA for inhibition and glutamate for excitation.

STROGATZ: All right. Now, can I have you unpack the ideas of inhibitory versus excitatory? You mentioned those ideas. What do you mean by that?

KRYSTAL: So, when you have a thought… Let’s say. You’re thinking, “What is Krystal talking about now?”, say. And, that thought is generated from one glutamate neuron or a bunch of glutamate neurons projecting to a bunch of other glutamate neurons projecting to a bunch of other glutamate neurons.

But those neurons, their activity is actually tightly tuned in terms of the magnitude of their activation and the timing of their activation by inhibition. So the brain generates information through excitation, but is tuned and becomes functional through inhibition.

Without GABA, the brain would be like a noisy TV set or radio, where you would hear all the background noise and it would be hard to figure out what the signal was. But the right balance between excitation and inhibition gives us a nice, clear information signal in the brain.

And that information might be an idea, but it also might be control of your emotion. And so, all the functions of the brain are influenced by this signal to noise property. And it turns out in depression those signal to noise properties become compromised in circuits involved in the regulation of mood, the anticipation of reward, in motivation and attention, and even, memory.

And so, when people become depressed, they don’t experience pleasure. There’s a disturbance in the reward and motivation circuitry. They have trouble focusing their attention. They have other symptoms that arise from the kind of noisy communication in the centers in the brain involved in the regulation of emotion.

The more we study the molecular biology of depression, the more we’ve come to understand that these changes are enormously complicated. And are partly arising from changes intrinsic to the pathology in the nerve cells, so that the pattern of genes expressed by that nerve cell are altered in a variety of ways. It happens in the glutamate nerve cells. It happens in the GABA inhibitory nerve cells.

But it also happens in other kinds of cells. There are cells called glia that support the nerve functions. Glia mop up the glutamate that’s released and make sure that there’s not so much glutamate floating around that it becomes toxic to the nerve cells.

There’s another kind of cell involved in the biology of depression, called microglia. Now microglia, that name sounds like they’re just tiny little glia, but that’s not exactly what they are.

Microglia are the brain’s immune cells. And it turns out that a process in the body called inflammation, which gives you sore joints, which contributes to your asthma, which may increase your blood pressure, in the brain activates the microglia, creates inflammatory processes in the brain, which compromise the structure and function of nerve cells and contribute to depression risk.

STROGATZ: Hmm.

KRYSTAL: The more we learn about the biology of depression, the more we realize that depression is a biology that involves many, many, many different cell types in the brain. And it’s linked to processes that contribute to disease in the entire body.

Why does diet help? Why does exercise help? Why does getting lots of sleep help? Why do all of these healthy activities, which are good for your overall body health. Why are they good for your depression health? It’s because a lot of the things that exercise does to promote health in your body, there’s a version of that going on in your brain.

STROGATZ: That’s great. That was a very illuminating discussion, the microglia, for instance, I had never heard of. I’d heard vague talk that chronic inflammation could affect so many things that we didn’t traditionally think of as just inflammatory diseases. What exactly is happening to the microglia, and how are they getting messed up?

KRYSTAL: So, microglia are some of my favorite cells in the brain these days.

STROGATZ: Ah hah!

KRYSTAL: A variety of stress hormones, they activate the microglia, and they in turn release pro-inflammatory substances like cytokines.

But one of the things that we’ve learned about microglia that make them so interesting to me is they are involved in the cleanup in the brain. They are surrounding the synapses just like the other kinds of glia are. And they can be involved in the protection of synapses, they can release nerve growth factors, or when they’re immunologically activated, they eliminate synapses.

And so we think that microglia are involved to some degree in a finding which is relatively new. If you look at people who have moderate to severe depressions, particularly persisting depression, and you use a technique called positron emission tomography, or PET scans, which enable us to quantify certain proteins in the brain, we can measure the density of synapses in the brain. And people who have moderate to severe depression show reductions in various parts of the brain in synaptic density, which tells us that these synapses are being eliminated.

We know a lot about synaptic elimination based on animal research. Severe kinds of stresses in animals cause the elimination of synapses in the brain and, in fact, can prune whole branches of the inputs, or dendrites, to a cell.

This was really an important insight because it helped to create a context for interpreting some basic neuroscience findings, which came from the laboratory of my late colleague and friend, Ronald Duman, and frankly another colleague who also recently passed away, George Aghajanian. Ron and George studied the effects of a drug that we had studied in depression called ketamine. We can come back to that in more detail, but we now have some very preliminary positron emission tomography data that suggests that single doses of ketamine can regrow these synapses in depressed patients.

What’s interesting is that a single dose of ketamine in a healthy person does not increase the density of synapses. A single dose of ketamine, though, regrows lost synapses. I like to think of it as a sign that this drug recruits resilience mechanisms intrinsic to the brain to restore normal brain structure and normal brain function as well.

STROGATZ: Going back to my childhood memories of learning biology, before I’m sure any of this was really understood, we were told the brain was not a plastic, changeable kind of thing. And so this idea that on a time scale of, I don’t know, minutes or hours after ketamine, I can start seeing synaptic regrowth — did I hear you right?

KRYSTAL: You’re absolutely right on both parts. Back in the 1970s — ancient history — you know, we didn’t have the tools that we needed in order to really understand, the brain’s capacity for plasticity.

These forms of neuroplasticity began to be worked out in the 1970s and 1980s. And then, really, with the advent of new kinds of basic neuroscience imaging, you can actually see these spines growing out of the dendrites, where they make the synaptic connections.

You realize, the brain is not static. It’s incredibly, unbelievably plastic. And it raises really fundamental ideas that it’s not just depression that we want to treat by harnessing neuroplasticity, but there are opportunities to treat other disorders that we don’t treat as effectively as we should.

STROGATZ: As soon as you start talking about — I think you used the adjective “spiny” — I feel like I remember learning somewhere that when memories are laid down, things may be happening at the level of dendrites.

KRYSTAL: Absolutely. Neuroplasticity is the vehicle for the storage of memories. And there are many different kinds of memories, right? There’s the memory that you have of where you went on vacation last summer. There’s the memory that you have about how to play “Für Elise” on the piano. And so there are these different kinds of memories that are stored in different circuits in the brain, and stored sometimes using different kinds of storage mechanisms. And these are really, really at the core of how we think certain kinds of treatments are working. So, for example, post-traumatic stress disorder is a maladaptive memory. Addiction is a maladaptive memory.

There are ways that what we’re learning about how to manipulate neuroplasticity, that we harness intentionally or unintentionally to treat these conditions, both through psychotherapies, and I think through the combination of plasticity targeting treatments in combination with behavioral therapies.

STROGATZ: We’ll be right back after this message.

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STROGATZ: Let me get back to ketamine. I mean, certainly some of our listeners will have heard of ketamine. It has, I have to say, connotations that are sort of unsavory if you hear about it as a drug on the street. I’ve heard it called a date rape drug, in its worst case, right? I mean — but then I also, just in preparing for our discussion, learned that in the Vietnam War, it was sometimes used for battlefield anesthesia, that you could help people who are severely, terribly injured. Anyway, you should tell us, I mean, maybe give us a little basic about ketamine first.

KRYSTAL: Sure. Well, clearly you’ve done your homework on this, because these drugs have abuse liability. Ketamine was the more practical stepchild of a more potent and longer acting drug that was developed in the 1950s, called phencyclidine or angel dust. And ketamine is a less potent and very short-acting drug, which does the same thing, which is to block one of the receptors for glutamate in the brain.

In other words, when glutamate is released, there are many different molecular targets for that glutamate. And one type of receptor for glutamate is the NMDA subtype. And it turns out that the NMDA glutamate receptor is a critical node in the brain for initiating neuroplasticity.

What’s kind of striking about ketamine is that while ketamine is reducing neuroplasticity while the drug’s in your body, it triggers reactions in depressed patients that enhance neuroplasticity, say, 24 hours later. And so, if you do cognitive behavioral therapy for depression, 24 hours later, for example, you can augment the therapeutic impact of ketamine. You can, you know, take advantage of this window, it seems, to promote therapeutic recovery.

Ketamine is doing many things for people with, say, treatment-resistant forms of depression, that are just triggered by the drug itself. For example, in depression we have evidence of at least three different kinds of pathology related to the glutamate synapse. One, the synaptic elimination that I mentioned earlier. Two, the synapses are not as functional, they’re less effective. And three, the glutamate that’s released is not handled very effectively because of the compromise of the glia and other factors.

And it seems that ketamine addresses all three of these forms of glutamate pathology: regrowing synapses, restoring synaptic effectiveness, and compensating for glutamate receptor overstimulation.

And on top of that, there are these opportunities for synergies with different kinds of psychotherapies targeted at different times in relation to the ketamine infusion. So, there’s a lot going on with this one little simple drug that seem like it may help depression, maybe addiction, maybe post-traumatic stress disorder, and certain other kinds of conditions.

STROGATZ: Well, I think this could be the point where we should mention that you are the co-founder of a biotech company exploring ketamine, called Freedom Biosciences. When you started it, what were you hoping to accomplish?

KRYSTAL: Like many things, this was a happy accident. We had been very interested in studying the mechanisms through which ketamine worked. We figured that if we truly understood deeply how ketamine affected the brain, then it might lead us to drugs that were more effective than ketamine, lasted longer than ketamine, had less side effects than ketamine, et cetera.

STROGATZ: So wait, you’re exploring ketamine to find drugs better than ketamine?

KRYSTAL: Yes. So, maybe we should back up a little bit to the history. So my colleagues and I first started studying ketamine around 1990.

STROGATZ: Uh huh.

KRYSTAL: In 1995, we first gave ketamine to depressed patients in a randomized controlled trial and discovered the rapid antidepressant effect. And so, the first time we presented our ketamine results in public was 1997, 25 years ago. And after that point, ketamine was studied by our group and many, many others.

A version of ketamine called S-ketamine was developed by Johnson & Johnson, now marketed as Spravato. It was approved by the FDA in 2019 as a medication for treatment-resistant forms of depression, and that was the first mechanistically novel antidepressant in 50 years.

It really was a profound step for the field and a remarkable kind of new treatment. First, it reacted rapidly. Instead of taking weeks to have effect, many people would have a clinical response or even remission within 24 hours after a dose.

STROGATZ: Unbelievable, wow.

KRYSTAL: Generally speaking, most antidepressant strategies work for about 10-to-20% of people who have treatment-resistant symptoms of depression. But ketamine is more like 50-to-75% of patients, so it’s a dramatically more effective kind of treatment.

The data collected by Johnson & Johnson suggests that ketamine may be something like twice as protective against relapse of depression symptoms once people respond than traditional antidepressant medications. In other words, 25 percent relapsing over a year as opposed to somewhere between 50 and 75% of patients that relapse on traditional antidepressants.

Two new pieces of data are extremely exciting that come from long-term follow up data. One, that S-ketamine long-term reduces all-cause mortality. In other words, it reduces suicide by about tenfold and it reduces all-cause mortality on top of that.

Depression is a part of your whole-body health. It arises from whole-body illnesses like inflammation. And treating depression contributes, like exercise and diet, to your whole-body health. This is an incredible thing. We have a novel medication which has really broad impact on not just depression but your overall health.

But this was a discovery that we talked about 25 years ago. And, you know, science is a restless process. You never, you never say, “We solved it. We’re done. We can go home. We can go on vacation,” right? We don’t do that because every time we — every time we make one kind of advance, it opens up 100 other questions that that we want to pursue.

STROGATZ: Well, stepping back, you know, in society, there’s so much depression these days among young people. We hear about rising rates of depression, and I just wondered if you had thoughts about that. What’s going on, any particular comments?

KRYSTAL: Well, you know, I, I, think that there is so much going on in this world, which is depressing.

STROGATZ: Hmm. Yes. No, it’s true.

KRYSTAL: And it’s, you know — things that have happened in the United States, the political turmoil that we’ve been through, the racial issues that we’ve been through in this country, the global wars that are going on. It’s pretty discouraging.

We’ve been through a period with Covid, where families have been terribly affected through loss or even extended serious hospitalizations of relatives and family members. And then on top of that the fragmentation of circles of friends, social connections, that we’ve had on an extended basis during Covid, I think has made us more vulnerable to all of the things we’re having to deal with in the world today.

And, you know, being a teenager is hard enough under the best of circumstances. And to go through all of this is really more than many can bear. And so, adolescents are one of the groups that had a particularly tough time.

STROGATZ: Sure. Well, let me, let me close on a lighter note then. So studying depression must be a pretty heavy experience for you personally, and I’m wondering is there something that lightens your load, that gives you joy in this work?

KRYSTAL: You know, it’s interesting that you should say that. I mean, it’s true, sitting with someone who’s in such extreme emotional distress can be a painful experience for the therapist. But the therapist, the psychiatrist, is the bearer of hope. And so every patient that I sit down with, I imagine them getting better and I imagine a path of treatment that we will go through together.

And one of the remarkable things about ketamine that can’t be quantified, but which I believe is extremely important, is that having this treatment that can be so effective for so many people helps the doctor and helps the patient not to give up.

There’s a study that was conducted in the 1990s that said that if you didn’t get better in the first year of treatment, the chances of getting better over the next four years were pretty low. It’s no longer the case.

We have effective treatments. We have ketamine, we have S-ketamine, we have electroconvulsive therapy, we have new forms of transcranial magnetic stimulation. We will soon have psilocybin for depression. We will probably have MDMA for PTSD. These are inspiring and hopeful advances that help doctors and help people getting treatment have faith that they will get to a recovery. That’s a really transformative advance just in itself. And something that I find every day inspiring.

STROGATZ: Well, thank you very much. We’ve been speaking with Yale psychiatrist [and] neuropharmacologist John Krystal about the causes and potential cures for depression. John, thanks so much again for joining us.

KRYSTAL: Steve, it was a pleasure. Thanks.

STROGATZ: If you or someone you know is struggling or in crisis, you’re not alone. Help is available through the 988 Suicide & Crisis Lifeline. Call or text 9-8-8 or live chat at their website 9-8-8 Lifeline dot org.

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“The Joy of Why” is a podcast from Quanta Magazine, an editorially independent publication supported by the Simons Foundation. Funding decisions by the Simons Foundation have no influence on the selection of topics, guests or other editorial decisions in this podcast or in Quanta Magazine.

“The Joy of Why” is produced by PRX Productions; the production team is Caitlin Faulds, Livia Brock, Genevieve Sponsler, and Merritt Jacob. The executive producer of PRX Productions is Jocelyn Gonzales. Morgan Church and Edwin Ochoa provided additional assistance. From Quanta Magazine, John Rennie and Thomas Lin provided editorial guidance, with support from Matt Carlstrom, Samuel Velasco, Nona Griffin, Arleen Santana and Madison Goldberg.

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I’m your host, Steve Strogatz. If you have any questions or comments for us, please email us at [email protected].