Dr. Carlos Zarate — Ketamine to Combat Depression

>> Newscaster 1: Millions of Americans suffer from depression that doesn't respond to medication, but for some the drug ketamine could be a breakthrough.

>> Newscaster 2: …ketamine. It's an anesthetic also used illicitly as a club drug and it's now being used by some doctors who have patients in a serious suicidal state.

>> Diego (narration): Ketamine is often thought of an illicit party drug—something people take for a momentary high. It can produce hallucinations and dissociative effects that alter the user’s perception of reality. People who have taken the drug recreationally and written about it describe the experience as, “entering another dimension,” or “an ongoing euphoria and silliness that [they hadn’t] felt since childhood.” Or perhaps even more perplexing, “like walking from your kitchen to your living room, and from your living room to your kitchen, and it’s uphill both ways, but you’ve never had so much fun walking up a hill.”

But ketamine wasn’t designed to be a mind-altering drug. It was originally developed and approved by the FDA as an anesthetic in 1970. Since then, it’s been used regularly in emergency departments, operating rooms and even dentists’ offices to relieve temporary pain.

And now it seems ketamine can provide solace not just from physical pain. The drug has found a new purpose as an anti-depressant treatment for people who have recurring suicidal thoughts and for whom other treatments have not helped. At the NIH, Dr. Carlos Zarate was part of a team that determined that a single infusion of ketamine can rapidly reduce depressive symptoms in people with treatment-resistant depression or bipolar depression.

Dr. Zarate is the chief of the Experimental Therapeutics and Pathophysiology Branch at the National Institute of Mental Health, where he focuses on developing new medications for this often-debilitating condition and identifying drug targets and objective measures that could yield could information about how a patient is responding to a treatment.

During my conversation with Dr. Zarate, we talked about how ketamine works to breathe new life into the neural circuitry of patients with treatment-resistant depression and what it means for those who have benefited from it after exhausting other options.

>> Diego (interview): So, Dr. Zarate you focus on developing novel medications for the treatment of depression and bipolar disorder. One of these medications is ketamine. Now people might be surprised to hear that since the early 2000s, it's been under serious investigation for its potential to help mental health patients. So how did ketamine find its way into research labs?

>> Dr. Zarate: Well, the finding of ketamine is one based on an early clinical observation in the late 1990s where a single administration of ketamine, which is an anesthetic agent leads to rapid antidepressant effects. Now, this was an observation, but was for many reasons not pursued largely because of its side effect profile. It produces symptoms of dissociation—one’s mind and body are disconnected from the senses. And the other concern for pursuing ketamine at that time was its abuse potential. So, for ethical reasons, when we originally began our research in ketamine, we studied patients who had been severely ill, had failed over six, seven anti-depressants, many had previous suicide attempts and had failed one of the most effective treatments for depression which is ECT or electroconvulsive therapy. So, for those subjects there were really no other treatment options. And so, we conducted a study with ketamine in the early 2000s and we found that a single administration in patients who failed six, seven antidepressants had a response within a couple of hours with a single administration and its effect lasted a week or two.

>> Diego (interview): Yeah, so one of the most promising things about using ketamine in the early studies, is how quickly the drug had a positive effect on the people that did respond well. And like you said, it took effect within hours and could have lasted like up to a week…

>> Dr. Zarate: Yes, one to two weeks.

>> Diego (interview): And that almost feels too good to be true, compared to the other treatments. Was there any like trepidation moving forward?

>> Dr. Zarate: Well, you are correct that when we had the original subjects, it was too good to be true, in a sense. It was a small, early, phase two study. So, we went ahead and did a series of other studies and found that indeed, the findings replicated. The onset and offset of the antidepressant effects—onset within a few hours and then it lasts one to two weeks—was nearly identical from study this study. That gave us the hint that possibly that we’re really tapping into the neurobiology of the anti-depressant effects of rapid onset. Eventually those single dose infusion studies, which were really proof-of-concept studies, were followed by multiple infusion studies where subjects or patients would get two to three times a week over the course of two to three weeks. And the rapid effects of ketamine appeared to be sustained during that period of time.

>> Diego (interview): So, you said that even one infusion is long lasting, right? But now there's treatments that have two to three infusions. What does a treatment look like, typically?

>> Dr. Zarate: Typically what happens is that patients are generally evaluated to determine that they are truly treatment-resistant, meaning they’ve failed at least two antidepressant drugs in a current major depressive episode. And that usually is established through interviews with family members, other providers, medical records. After that, if it’s deemed that our patient would benefit from the use of either intravenous ketamine or intranasal form of ketamine, they generally receive two to three administrations two times a week over two weeks. If there is benefit within that period of time, and then it’s established, one reaches a frequency of administration which varies from person to person—each individual is different—but it could be spread out over every month or two months, a single administration. Now, there are some unknowns in terms of what is the risk to subjects receiving ketamine long-term who have a mood disorder or psychiatric condition. It has really not been put together in large systematic studies and so that work is underway.

>> Diego (interview): Even so though, it seems like it's very promising. I would assume that it's also a huge relief for patients who do experience positive effects from the treatment.

>> Dr. Zarate: Oh, you are correct. We've had patients who have been twenty, thirty, forty years really incapacitated from depression, multiple hospitalizations and suicide attempts. You don't know if your loved one is going to be alive or dead. And they’ve tried many treatments; talk therapies, medications, ECT, and for some, not all, but for some, it makes a big change in their life. And so, that has been really rewarding to see people get back with their lives [sic] or families, get back together you know they were falling apart. So that that has been a tremendous relief and you know it is a deadly illness. There are individuals who will die of suicide. The life expectancy for people with chronic severe mental illnesses could be six years seven years eight years less than people without chronic mental illness. So, it does make an impact. Perhaps these newer treatments could start earlier in the course of illness and thus prevent all those years of morbidity and risk of mortality.

>> Diego (interview): Yeah, hopefully. Well, so these feelings that the patients feel now—so the more stable state of mind, if you will—it’s because ketamine acts differently than other anti-depressant medications, is that right? Like Lexapro and Prozac which are selective serotonin reuptake inhibitors, so SSRIs. Can you describe how SSRIs work in the brain and how ketamine differs from that?

>> Dr. Zarate: Yeah, so selective serotonin reuptake inhibitors are drugs that would be believed to be a bit more selective. So, we have presynaptic receptors and then postsynaptic receptors. That means these are receptors in the synaptic cleft or the space where the neurochemical flows from one neuron to another. And so, what is believed is that the SSRI some of them bind to this reuptake protein which is the thermostat that regulates the amount of serotonin that goes into that synaptic space. It’s believed that’s decreased the serotonin in that synaptic space and so the SSRIs inhibit that thermostat so permitting that it's not picked up again or that there's not a recycling into the presynaptic neuron but stays in that synaptic space.

>> Diego (interview): Yeah.

>> Dr. Zarate: Now, what ketamine does is predominate in the glutamate, which is an excitatory amino acid. One of the most predominant in the central nervous system. And it's very important in processes of synapse plasticity, meaning where one neuron talks to another, there's this gap of space that's really very tiny, but when you have a series of synapses that connect, you have intact circuits. And so, the chronic stress or excess glutamate or other insults over the years, it's believed that leads to this atrophy of synapses and circuits. It's not that they die, but they're shriveled.

>> Diego (interview): Ok…

>> Dr. Zarate: Ketamine and other treatments—next generation—are going to be plasticity enhancers. So what they mean is, they insert these subunits of these proteins into the synaptic space, and they let the synapses and circuits become healthy again. The analogy I use is that you have a tree in spring with branches and leaves, and it looks very healthy, and some of them might have flowers. And what happens is, you have the rain and the moisture that leads the branches to sprout. What's believed happens in depression, is the synapses and the circuits look more like trees in the winter. The leaves drop, and the branches and the buds.

>> Diego (interview): Got it. So shriveled and kind of like --

>> Dr. Zarate: There’s a shriveling. So, what ketamine or other treatments are what we call the miracle growth factors. Miracle-Gro is what you use in your garden.

>> Diego (interview): Yeah.

>> Dr. Zarate: That's kind of the more simple, general explanation on [sic] how things are. Of course, it's much more complex, but that's at least a visual way of explaining what necessarily happens in depression—where it's not necessarily that the synapses and the circuits die, but they're just shrivele. Whereas in degenerative conditions such as Alzheimer's, you know, some of those can die and you can’t get bring back. And so, that's believed, in part, to be excess glutamate. So, the simple theory of, we have too little serotonin or too little norepinephrine, it's much more than that.

>> Diego (interview): What does glutamate actually do? Let’s say I’m a person who doesn’t have a psychiatric disorder.

>> Dr. Zarate: Yeah. Glutamate is a molecule –it’s an excitatory amino acid. It's important for normal function. And it's, you know, learning, memory, the plasticity process, how one neuron talks to another. Very important. It's involved in maintaining the trees, you know, healthy, I mean, the leaves the axons and the buds. But it's also—there are other neurochemicals, like GABA, which kind of helps regulate. That's the inhibition. Ketamine's the excitation. So there's this ying-yang, this interplay between those two. And then with all the other neurochemicals; the serotonin, the norepinephrine, dopamine. So, it's very complex interplay, but, you know, at one level, it appears that the effects of ketamine are predominantly through glutamate. But once you affect glutamate, you have this wide systemic effect on other neurochemicals.

>> Diego (interview): So ketamine essentially acts on a post-synaptic never, specifically on a receptor on the post-synaptic nerve?

>> Dr. Zarate: Yes, the NMDA receptor and AMPA receptor. And just keep in mind, those are the keyholes into the room, right? So, if you take the analogy of, if you were in New York, you have one building, and across the street, another building and another building and another building. You could argue that each of those buildings are synapses or circuits. Because, you know, what happens is, you have one synapse, right, which is one building, but then underground, you may have the wires and sewer systems and the pipes, and those could be the circuits. But when you go to specific building, you have a keyhole and a lock, right? And inside that building is what we would call the cell, right? And then you have a coffee machine – you might have a generator there, that's the mitochondria, the energy pack for the entire building –and you have other rooms that have different functions, right? Sorting information, you know, if you get mail, it goes to the mail room and it's sorted. So, some of those rooms within the building might be responsible for the efficacy of ketamine, and others might be responsible for the side effects. So we wanted to try to find which of that room is important.

>> Diego (interview): So right now, we're just blocking the door, but that obviously has repercussions within the so-called building, and you are trying to narrow down which room to go into --

>> Dr. Zarate: Yes. Exactly. And so, we kind of want to avoid the traffic in the rooms that have nothing to do with what we want to [inaudible] functionally. You know, you want to go straight to your office and your desk and start to get on your computer and work. You don't want to have to go through different places and cause disruptions. So, in the future, we're going to get to that point. What we know now, with the SSRIs, literally, is that the building we were going into is really not that building, but the building across the street. And that's when we get to the reuptake protein. So, the serotonin could be the person who delivers coffee to the building that we're interested across the street. With the reuptake inhibitors, we regulate the amount of coffee that's coming from the street across. And all of a sudden, we have a lot more coffee and everybody can function in the building. Now, that's a bit more selective. But what ketamine might do is, it goes to the building across the street, to the building we're in, and into every other building in town. So, the entire city is affected at the same time.

>> Diego (interview): Got you. And is this mechanism of action that we're talking about, is that the reason why it could help people who experience that global inability to feel pleasure? I think you called it anhedonia.

>> Dr. Zarate: Yeah. And so, keep in mind that depression is very heterogeneous, meaning it consists of many other symptoms and syndromes and conditions. So both you and I could have major depressive episodes, but we might not overlap in any of the symptoms. I could be eating a lot and sleeping a little, and you could be eating very little and sleep all day long, you know. And yet we meet major depressive disorder. That's what we refer to as heterogeneous. And so, we and others are trying to do is come up with more homogeneous subgroups. So, going back to the entire city of New York as depression, some neighborhoods or villages there will be responsible for anhedonia, others for anxiety symptoms. So, you could see that coming up with one treatment like ketamine or ECT, electroconvulsive therapy, can affect the entire city of New York at the same time. So, your symptoms of anhedonia, anxiety improves; but what we're trying to do is trying to is divide that big city into different subgroups. Not each village, each neighborhood requires the same thing.

>> Diego (interview): Right. They're different. That makes sense. Well, I kind of want to touch now on what you were talking about, the risk for potential abuse. Because ketamine, or rather, s-ketamine -- similar drug, I guess, or derived from ketamine -- was approved by the FDA last year. And like you said, it's now sold as Spravato in the form of a nasal spray. Considering what's happened with the opioid crisis, is there a risk for, you know, ketamine abuse or over-prescription of ketamine?

>> Dr. Zarate: We do know that there is a potential risk of abuse with ketamine. That has been known for over 50, 60 years. Ketamine is used very commonly in emergency room settings. Internists use it. Anesthesiologists use it for anesthesia. For diagnostic purposes in emergency room. You may know it's listed by the WHO, World Health Organization, as an essential medication. Ketamine is used in the most remote parts of the world where they don't have an anesthesiologist or a physician, and nurses give ketamine. So, it does help people in those conditions. Its use is strictly monitored. For example, Spravato is strictly monitored and can be administered only in medical settings, under people trained on its use. It’s not given for you to take home. There’s a specific program for that. And intravenous ketamine is given the same way. But nevertheless, it is a concern. We want to come up with a better form of ketamine.

In a collaboration with University of Maryland, Todd Gould, with the NCATS, National Center for Advanced Translational Science; and Craig Thomas, Ruin Moaddel at the National Institute of Aging, NIA, Patrick Morris, we've pursued the metabolites of ketamine and in preclinical studies, we've found that it does not have what would be predicted to be the side effects of ketamine or the abuse potential. And so, in a multi-institute effort –several institutes are involved at NIH and with the University of Maryland—we’ve been developing this drug. It is starting phase one as we speak, and we plan to test the intravenous form of it hopefully sometime summer next year to see if it does have the antidepressant effects of ketamine without the side effects and abuse potential. If so, that would be a game-changer because we could then give it to people earlier in the course of illness without that risk.

>> Diego (interview): Great. Are there any other drugs or maybe any classes of drugs that are on the horizon for treatment of depression?

>> Dr. Zarate: Very recently, there has been success at the GABA side of the equation, the inhibition side. In a recent drug which affects GABA-A receptor found that it produced a fairly rapid and anti-depressant in women with postpartum depression. It's now approved on the market, brexanolone, for intravenous use in women who have postpartum depression. The manufacturer of the company is now developing an oral form, a pill form, of that to see if it works in major depressive disorder. So, this past year has been one of considerable success, 2019, approval of ketamine, approval of brexanolone for postpartum depression. There was another device, a neuro-modulation device, approved for use in depression as well. And that has to do with a lot of work that's funded by NIH and NIMH—these partnerships with academics, government, industry has led to a better understanding of the neurobiology, what might be important in depression, but we still are at the beginning. We need a lot more information before we can come up with better next-generation treatments. But, you know, the infrastructure is there to move forward and to succeed and we and others are going to continue to push for it to get better treatments for our patients.

>> Diego (interview): Yeah. I mean, you mentioned that it's a lot of the funding from NIH and NIMH, but it seems that public opinion around these so-called party drugs is slowly shifting with the destigmatization of mental illness. I mean, Oregon just decriminalized possession and personal use of all drugs. I would imagine this gradual ceasefire on the war on drugs must be opening a lot of doors for new research and funding opportunities.

>> Dr. Zarate: Yeah. I do think that many of these drugs we have known about for many years: psilocybin, LSD, MDMA, of course ketamine, and are very popular as a psychedelic therapy, you know, way back in the '50s and '60s. And, of course, as you mentioned, there were government regulations to prevent its use or its study or they're tightly controlled and regulated. But the findings of ketamine, I think, have opened a gate to considering other psychedelic treatments. And as you pointed out, many of these are now in phase two, phase three for many different conditions; for PTSD, they're being looked at for treatment-resistant depression as well, you know, obsessive-compulsive disorder, so many of these debilitating conditions. And so, I do think these treatments could have the potential of being, you know, approved. But also, we can learn more from them in terms of mechanism. You know, to design better-tolerated drugs, such as we're following the path with ketamine. So, I think that's going to happen with other psychedelic treatments. But there is now a willingness to consider these alternative treatments. But certainly, we don't want to jump into some of these drugs when there might be other alternatives. It’s important to consider talk therapy. Some of the older antidepressants may still prove useful for many. So, I think we're going to have to partner, you know, with industry, academics, and government, private practitioners and patient advocacy groups to make sure we have a dialogue on the findings and when we should release different treatments and what conditions.

>> Diego (interview): Of course. Well, another main focus of your lab is identifying biomarkers that could be used to determine whether a person is either a good candidate for treatment with these specific compounds or to inform how they respond. Can you maybe talk a little bit about that?

>> Dr. Zarate: Yes. The intramural program at NIMH, NIH does have these different core groups that permit us to obtain technology in different areas to better understand the biology at different levels, going from behavior through neurochemical, circuits, cellular, molecular, all the way down to genetics. And so, we can do a very deep phenotyping at the biological level, integrate it with clinical and, of course, the social environment to better understand how all this goes together in our patients that suffer from depression.

The older studies used to take a scan of somebody's brain when they're depressed versus healthy control. And we would, you know, try to learn something--we do learn something from that. But we do know that the brain is a very plastic and dynamic. What we do now is examine all those different modalities, technologies in the depressed or suicidal brain. And not only that, we also obtain all those measures in individuals when their symptoms of depression return, so they’re kind of back to baseline. And so, we can see the on-off-on effects of ketamine. then examine these different processes going on in the brain and the body in the same individual. And we think that's going to be a very powerful approach, giving clues on how ketamine might work in the brain and the rest of the body. So that’s what we refer to as biomarker work. Some of those might be useful in overlapping with the standard, conventional antidepressants, right? And then others will be different, and we can start sorting those now.

>> Diego (interview): Well, I don't want to take up too much of your time, but I'm curious, how did you get your start and what was the motivation for you to get into all of this? And what led you to the NIH?

>> Dr. Zarate: Well, it's a long process, but I was very interested in research. I was at the Brockton VA in the consolidated department of psychiatry in Harvard Medical School. And I was interested in research, was going to pursue genetics and epidemiology, but in my second year of residency, I fell in love with psychopharmacology and started participating in clinical trials, recruiting subjects for other investigators and I learned in the process that this is so cool. And I started brushing up as much as I could as a resident in psychopharmacology. Eventually, I went to McClain Hospital into Harvard Medical School, where I pursued a fellowship in clinical psychopharmacology. We then started – I had started taking care of a clinic and literally had hundreds of patients with bipolar disorder, schizophrenia, and schizoaffective disorder, and saw the tremendous amount of suffering, but, you know, I'm very thankful for getting to know them and trying to help them and their families. But I do recognize that we had limitations on how effective our medications were and side effects. So, my boss back then decided to pursue experimental therapeutics and try many of the drugs that are now on the market and study them with industry, of course, but as a site for one of these multi-site studies with novel therapeutics in schizophrenia, psychosis, mania. I got involved, and I said, "Wow, this is interesting." And so, I started getting involved in that aspect of it, and eventually, I went to UMass for a couple of years. Really appreciated what they did, and I led the bipolar and psychiatry disorders program, but what was missing was neurobiology and neuropsychopharmacology; really getting at the biology of what's going on in the patients. And I did read on that, but they didn't have much of the training. I was asked, "Do you want to come to NIH, have a research unit, and do experimental trials and look at novel drugs?" And I said yes, and that was 20 years ago.

>> Diego (interview): Yeah. Well, recently, you were inducted into the National Academy of Medicine, so how does it feel to, you know, hit such a milestone in your career?

>> Dr. Zarate: Yeah. I'm very honored. You know, I couldn't have done it without the support, of course, of my family, who've been very tolerant. But they really get it and, you know, believe that it's important to serve. But NIMH, NIH has been fantastic in supporting my career, you know, my development, and, you know, it could have turned out that maybe we didn't find anything, or we did. But either way, it's a journey and path we're taking together, so I'm very appreciative for all they've done. And if there are trainees out there, it's such a cool place with all these gadgets and technologies, and it's really at the forefront. And there’s a tremendous sense of family, collaboration and, you know, common goal and mission to try to find better things for our patients. And, you know, we're contributing. We could do much more, but it is a really cool place.

>> Diego (interview): Yeah. Great. Well, thank you so much for this very, very interesting conversation.

>> Dr. Zarate: Well, thank you, Diego.