#           Mental Health Matters Podcast:        Depression: The Case for Ketamine  

October 3, 2023 • 75th Anniversary

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## Episode Summary

Ketamine. For some people with treatment-resistant depression, this experimental therapy proved to be more than just life-changing—it was lifesaving. But how did a drug once used as a battlefield anesthetic evolve into esketamine, a treatment for major depressive illnesses? In this episode, we'll talk with Dr. Carlos Zarate Jr., who helped lay the groundwork for esketamine for treatment-resistant depression. We'll learn the history behind the development of esketamine, how it can help with depression, and what the future holds for this innovative line of clinical research.

## Transcript

**Dr. Zarate:** The notion had been that you have to give a medication every day for six to eight weeks, and maybe you might feel better. And that was a believe to be necessary. You had to do this. And when our patients started with ketamine, all of a sudden we saw in a couple of hours, they were what would stake in 10 to 12 weeks with our standard antidepressants. We were, "Wow. This is incredible."

**Dr. Gordon:** Ketamine. For some people with treatment-resistant depression, this experimental therapy proved to be more than just life-changing. It was life-saving. But how did a drug once used as a battlefield anesthetic evolve into esketamine, a treatment for major depressive illnesses? Hello, and welcome to "Mental Health Matters," a National Institute of Mental Health podcast. I'm Dr. Joshua Gordon, the director of NIMH. And today, we'll be talking with Dr. Carlos Zarate Jr. who helped lay the groundwork for esketamine for treatment resistant depression. In this episode, we'll learn the history behind the development of esketamine, how it can help with depression, and what the future holds for this innovative line of clinical research. I'm joined today by Dr. Carlos Zarate. We're gonna talk about depression. Welcome, Carlos. Depression is one of the most common mental disorders in the United States. What are its hallmarks?

**Dr. Zarate:** First of all, thank you for having me today. Major depressive disorder is one of the most common and disabling mental disorders in the world. It is characterized by combination of symptoms that includes a persistent sad mood, diminished self-worth, lower self-esteem, difficulty concentrating, fatigue, disruptions to one's sleep, and inability to experience pleasure. Furthermore, all these symptoms generally last weeks, months, or longer and affect ability of an individual to function adequately and to connect well with their family and to society. Also, our patients who suffer from depression are considered at risk of self-harm.

**Dr. Gordon:** How is it usually treated?

**Dr. Zarate:** In terms of how it's treated, there are generally three general groups of treatments. So, we have the psychotherapies. We have medications, and we have what we call narrow stimulation devices. And within each of those classes, we have many different options. And, for example, within the talk therapies, we have psychotherapy such as cognitive behavioral therapy, mindfulness. Within the medications, we have a long list of medications. Some of them tap into certain neurotransmitters such as serotonin, and we refer to that as selective serotonin reuptake inhibitors. And then we have the group of neurostimulation. We may use transcranial magnetic stimulation, or we may use ECT or Electroconvulsive Therapy. It's not unusual for patients to receive any combination of these different treatments to try to get them to a better spot.

**Dr. Gordon:** So, we have lots of different treatments for depression. Now, your own research has focused in on one of them, a relatively new treatment for depression called ketamine. What is ketamine? Where does it fit into the picture of different treatment options that we have?

**Dr. Zarate:** Well, ketamine is a medication that is used for anesthesia and also for treating chronic pain. It is approved by the Food and Drug Administration or FDA for anesthesia. It has been around for over 60 years. And more recently in 2019, it was approved form of ketamine called esketamine for treatment-resistant depression. And so, what ketamine does quite differently from the standard antidepressants... The standard antidepressants affect neurochemicals in the brain called serotonin and norepinephrine. Ketamine seems to focus on another chemical in the brain called glutamate. And glutamate is an amino acid that's important for the communication between the brain cells. It is now an option for treatment-resistant depression.

**Dr. Gordon:** So, treatment-resistant depression is when someone has a depression that doesn't get better after a couple of different treatments.

**Dr. Zarate:** That is correct.

**Dr. Gordon:** Now, ketamine is a drug that you've been studying for a while that may be effective for treatment-resistant depression. How did you get to that point? How did you get interested in research in this area? What inspired you?

**Dr. Zarate:** Well, I got interested in the research after treating for many years, hundreds of patients with bipolar disorder, treatment-resistant depression with the existing conventional antidepressants and psychotherapies, which were considered state of the art. It was clear that many would improve. But still, many more would not improve and had what we call treatment-resistant depression. And so, I started getting interested in what we call experimental therapeutics. That is developing new treatments that are much better than existing treatments. And so, then in the year 2001, a program was created at the National Institute of Mental Health, NIMH, in experimental therapeutics. And what we decided back then as a program is to go in a different path. The majority of the antidepressants had been developed based on an older drug that was used to treat tuberculosis. And what was noticed back then in the mid-1950s is that the individuals who had a lung infection, tuberculosis, generally, would have an improvement in their appetite, their energy, their wellbeing. And it occurred through clinical observations of very bright people back then that perhaps we can study this drug a bit more. And that led to the theory that serotonin and norepinephrine is affected. And from that time on, drug development was based on drugs very similar that they could regulate serotonin-norepinephrine levels, and they all had antidepressant effects. The problem is that most of them were pretty similar. And this gets back to my experience in the clinic. Generally, many individuals would have what we call treatment-resistant depression. And so, we had to go into a new direction. And that's where in the year 2000, we decided to go at the glutamate path, pursue this new chemical glutamate, which is important in communication between cells learning and memory.

**Dr. Gordon:** Ketamine affects the glutamate system. And you said glutamate is the main communication chemical between neurons. You also mentioned two other, what we call neurotransmitters, serotonin and norepinephrine. What do they do?

**Dr. Zarate:** Yeah. There are many different neurochemicals that are being studied in depression. One of them is serotonin, the other is norepinephrine. And then a third, for example, dopamine, and our medications have been developed based on that. They're involved in emotion. They're involved in mood. They're involved in sleep. They're involved in many important functions.

**Dr. Gordon:** Many functions by the way, that are disrupted in individuals with depression, right?

**Dr. Zarate:** Yes. Many of these functions are all disrupted in individual with depression. And what happens is that the way ketamine works is it produces this massive surge of glutamate that rapidly restores these neurochemicals and the circuits that are affected because of stress and depression over the years. Glutamate can do it almost immediately within hours. But serotonin and norepinephrine, these other neurochemicals, do so in a very indirect and long manner.

**Dr. Gordon:** How does ketamine work?

**Dr. Zarate:** Well, what we know of, first of all, how depression it is believed that depression produces in the brain shriveling of brain cells or neurons, which are important for the communication and many of the important processes as emotions, and learning, and memory, and activity levels. And this is due to stress and other insults. And what happens is that if one were to consider that the brain is a very rich network of these brain cells that they all speak and interact with each other, they're shriveling, and the information flow doesn't happen as well as it should be. The analogy one could take is, for example, a forest. You could have a forest that has many trees, and each of the tips of these trees touch each other's tip. And that could be an area where we call a circuit. And it's a dense network, which one tree communicates with the other tree. And, of course, it needs to transmit information from one tree to another tree. And that's what the brain and the cells look like. But what happens is with chronic depression and the insults is there's a shriveling, and the trees, which very healthy in spring, start looking more like trees in the winter. And so, what happens is that our antidepressants affect serotonin can restore some of these branches and leaves. So, it starts looking like a tree in spring, but it does so in a very indirect and long manner. But ketamine, a drug that regulates glutamate, can do so almost immediately within hours. And so, that is quite exciting and intriguing on how ketamine does that compared to our standard treatment.

**Dr. Gordon:** Now, a medication was recently approved by the U.S. Food and Drug Administration back in 2019, and it's called esketamine. What's the difference between ketamine and esketamine?

**Dr. Zarate:** Well, ketamine has a chemical structure that consists of two parts, one is called R and S. They're two components or what we called enantiomers. Enantiomers are the structures that are mirror images of each other. If you superimpose your left and your right hand, they look identical. They're mirror images, but they're not superimposable.

**Dr. Gordon:** I'm looking at my left and right hand. And right, there's a different structure to them.

**Dr. Zarate:** And so, what happened is that one of the companies who went on to develop ketamine took the S, and that's what's known as esketamine. And eventually, it was studied and approved for intranasal or squirts in the nose use.

**Dr. Gordon:** So, ketamine is like having both types of hands, left and right. And esketamine is like having only just right hands. Got it.

**Dr. Zarate:** Yes.

**Dr. Gordon:** Okay. Now, esketamine, like ketamine, also works more rapidly to help people with depression?

**Dr. Zarate:** Yes. Esketamine works as rapidly. It is proved by the Food and Drug Administration, FDA, in 2019 for two indications, one is treatment-resistant depression for individuals who have failed many different treatments, and also for adults with suicidal ideation or behavior. And so, that is approved, whereas the R and S ketamine, the racemic is not approved by the FDA, but it's used off-label. That means it's usually approved for another indication, but doctors prescribe it for the management of depression.

**Dr. Gordon:** So, regular ketamine, although it's used for depression, it's used off-label, meaning doctors are prescribing it. But the FDA hasn't officially said, "Yeah, this works for depression." But esketamine, that is FDA-approved for depression?

**Dr. Zarate:** Well, esketamine produces many of those changes in the structure and function of neurons within hours. And so, if you take the analogy of the tree in the winter, looks like a tree in the spring within hours, whereas the standard antidepressants that affect serotonin-norepinephrine do so in weeks.

**Dr. Gordon:** Now, in addition to doing the research, of course, Carlos, I know that you take care of these patients that have received ketamine and esketamine. What have your patients had to say about these fast-acting treatment-resistant depression treating drugs? What have they said about it?

**Dr. Zarate:** Yeah. It's fascinating that we referred patients from different states from around the country. They come to us. Of course, you could always find one individual that responds, but when it happened over and over again. So, what we notice is that not everybody responds. About half of our patients respond to ketamine, but those are patients who had failed a lot of different treatments. So, that is very important to know. And it's almost the depression if you respond lifts and it's removed. And that is incredible. So, if you had the persistent mood, the inability, suicidal thoughts are removed very instantaneously within a matter of hours. And that is quite remarkable. More importantly, it was only with a single administration we found that.

**Dr. Gordon:** So, you had patients that were ill for years that had real significant, serious symptoms. You saw them get better in a matter of what, hours?

**Dr. Zarate:** And keep in mind that we have patients who have recurrent depression that comes and goes over the lifetime. And we also had patients who had been depressed 20 to 30 years from the beginning, never were functioning and recovered. And some of those were improving. And older theories had it that that would be impossible to get better, and suggested that perhaps the brain is shriveling more and more as time goes by, and that those patients who had that type of depression would not get better after 20-30 years. But some of them did. So, that challenges existed notions of that this is not a downhill course of chronic depression.

**Dr. Gordon:** It must have really made you think differently about depression as a whole when you saw this happening.

**Dr. Zarate:** Well, yes. I mean, it was from developing new treatments. We were looking for treatments that would take 10 weeks, 12 weeks, and all our studies were designed in that manner. And all of a sudden, when you have people responding within a few hours, few days, at most, you say, "Wow, this really shakes our prior notions. We have to develop new trials, new ways of studying these medications." We can study biomarkers within a matter of hours or days. Biomarker means ways such as brain imaging of looking at the brain in real-time. So, really different, how do we measure the improvement very rapidly? When our patients got better, it was also their sense of, "I feel I can go back to work." And that would happen within hours. And usually, that would take years to get some of our patients back to that point.

**Dr. Gordon:** So, you're really transforming lives with this treatment?

**Dr. Zarate:** Yes. I think that for some patients, it really transforms their lives. It gives them new possibilities. It helps them reconnect with their family. It helps them reconnect with society to be a productive member, to continue with their family. Many of these things, their connection with family, their relationships, their jobs have been on hold for many years. They were living in isolation, in the dark, in their room, not going out, not having friends. And for some who got better, they have a new chance.

**Dr. Gordon:** So, Carlos, what are some of the challenges of using esketamine? Are there side effects? How is it given?

**Dr. Zarate:** Yes. So, some of the challenges of esketamine includes its side effects in misuse potential or abuse potential. So, in terms of the side effects of esketamine, one can have rapid increases in blood pressure and heart rate and what we call a dissociation or altered state of consciousness. These are transient side effects that go away right after esketamine is administered, usually within an hour or two hours. The other risk of esketamine is its misuse because it's a drug potentially of abuse. And so, for that reasons and because of the side effects, esketamine or Spravato is given in a doctor's office by a trained clinician who knows how to administer and monitor for these side effects.

**Dr. Gordon:** So, if I'm someone who walks into my doctor's office and we decide together esketamine is right for me, what does the experience of getting esketamine look like for me?

**Dr. Zarate:** So, usually, the trained provider of esketamine will have been in contact with your doctor or your clinician, make sure that you have tried previous treatments. The next is they will do a full assessment to make sure you suffer from treatment-resistant depression, and also go over your medical history to make sure that your blood pressure and other health factors are in check and are stable enough that you could receive esketamine. And if so, that's usually an evaluation, what we call a screen evaluation that can last an hour or so. And if you're determined to be eligible for esketamine, you would be scheduled for an appointment. You would come in and you would receive it intranasally, the device where you put it in your nose, your nostril, and it provides one or two squirts of the medication into each nostril. And you get the different doses based on that.

**Dr. Gordon:** So, you squirt a little of this medicine in your nose, and then what happens? Because you're in the doctor's office, and you might have side effects.

**Dr. Zarate:** Yeah. The medicine is rapidly absorbed and goes to the brain, and then they monitor closely. You're in a comfortable chair. You have somebody there with you. They monitor your blood pressure. They monitor your pulse, and they help prepare you that you might experience these altered states of consciousness where your mind and your body might be disconnected. Time around you might seem unfamiliar, and you might have some numbing sensation in different parts of the body. So, you're really prepared and explained what happens. And then those side effects go away usually within one hour of the squirts in your nose. And then what happens is you can go home, but usually, you have somebody come and pick you up and take you home. Yeah. So, you're monitored through the entire process by a trained professional. And after that, even if you don't respond, you would come again for a second administration that week. And it's usually you received two treatments every two weeks for this first several weeks.

**Dr. Gordon:** So, can you help our listeners understand why you mentioned that esketamine is given into the nose because it gets into the brain faster. But that doesn't quite make sense to me. Why does squirting something into the nose get it into the brain that much faster?

**Dr. Zarate:** Yeah. So, there are these blood vessels within the nose that connect really with important brain structures that are right there. And so, it absorbs very quickly. Whereas if you were take it by mouth, ketamine, a form of ketamine, racemic ketamine does not absorb well in the gut. And so, what we usually do is use either as esketamine, the nasal squirts, or you can give it through a venous line, a little plastic tube in your vein to administer it more directly. In those two ways, the drug gets very quickly to the brain.

**Dr. Gordon:** Gotcha. So, it's all those blood vessels in the nose that really help that get collected so quickly. What's one thing that you'd want people listening to understand about esketamine?

**Dr. Zarate:** Yes. I think it's important to understand that esketamine is not for everyone. I think it's important. Not everybody will respond. Half will respond who have treatment-resistant depression. Esketamine or ketamine is not a cure. Sometimes in the media, it's touted as something that will cause a cure. That is not the case. What will happen is if you respond, you'll notice a rapid improvement of the symptoms that have been impairing you. And to maintain the improvement, you will need to have the treatment administered a few times a week for several weeks. But you will still need to continue with perhaps other medications that we talked about or psychotherapies for the long term. The other important thing to know is that ketamine is approved by the FDA, whereas the other types of ketamine are not approved by the FDA. They're off-label use. And the final point of this is that we can develop new and better treatments through further research. And that work is underway.

**Dr. Gordon:** Ketamine, esketamine, these are exciting new developments. What's next for depression treatment? What does the future hold?

**Dr. Zarate:** Yeah. With regards to esketamine, we provide a new treatment option for our patients. And many will improve who have treatment-resistant depression. But also gives us a prototype of a model where we can begin to study how does it work in the brain? And if we can figure out how it works in the brain, we can come up with next or future generation treatments. And through advances in chemistry, we can start figuring out what are the parts of esketamine or ketamine that cause the side effects and the other parts that cause the improvement? And we can then develop treatments that work very rapidly with ketamine, but do not have the side effects or abuse potential. That is our hope. And work is now underway to try to do that.

**Dr. Gordon:** Is there a moment in your career where you've really seen that hard work pay off?

**Dr. Zarate:** I would say the field has taken off literally overnight with the find of ketamine that has rapid antidepressant effects in a few hours in people who have failed many treatments. And also, rapid improvement in their suicidal thinking that really is improved. And that has opened the possibility, the doors to other clinicians, to patients, their families, to get access to these new treatments. And to researchers, we can gain better knowledge through understanding how this works. We can develop better treatments. So, really, I think that's a pivotal moment that really in my lifetime, you know, I don't know if I'll ever experience anything similar. But I'm just quite happy that we have been able to give that opportunity to our patients and to next generation researchers to come up with the cure for these illnesses.

**Dr. Gordon:** It must be incredibly rewarding to see your work have that kind of impact.

**Dr. Zarate:** Yes. And keep in mind that it's been extremely rewarding, but really, my reward is to really see my patient getting better and smiling. They hugging each other and saying, "Gosh, we're out of this." Still, it's not a cure, but they have a lot of work to go. But I wanna see many more smiles and more hugging over the years.

**Dr. Gordon:** Well, Carlos, thank you so much for joining me today to talk about depression and ketamine and the fascinating work that you've done.

**Dr. Zarate:** Thank you so much for inviting me today to talk about this important area of discovery and research in the topic of depression and esketamine.

**Dr. Gordon:** This concludes this episode of "Mental Health Matters." I'd like to thank our guest, Dr. Carlos Zarate, for joining us today. And I'd like to thank you for listening. If you enjoyed this podcast, please subscribe and tell a friend to tune in. If you'd like to know more about esketamine, please visit nimh.gov. We hope you'll join us for the next podcast.