Dan Iosifescu, MD, is an Associate Professor of Psychiatry at the NYU Grossman School of Medicine and director of clinical research at the Nathan Kline Institute for Psychiatric Research. His research has led to the validation of novel treatments for patients with severe mood and anxiety disorders, including pharmacological treatments such as ketamine and other glutamatergic drugs, and devices such as novel forms of magnetic stimulation.
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Dan Iosifescu, MD, is an Associate Professor of Psychiatry at the NYU Grossman School of Medicine and director of clinical research at the Nathan Kline Institute for Psychiatric Research. His research has led to the validation of novel treatments for patients with severe mood and anxiety disorders, including pharmacological treatments such as ketamine and other glutamatergic drugs, and devices such as novel forms of magnetic stimulation.
Topics covered:
Visit our website for more insights on psychiatry.
Podcast producer: Jon Earle
[00:00:00] DR. THEA GALLAGHER: Welcome to NYU Langone Insights on Psychiatry, a clinician's guide to the latest in psychiatric research. I'm Dr. Thea Gallagher, a clinical psychologist and assistant professor at NYU Langone. Each episode I interview a leading psychiatric researcher about how their work translates into clinical practice. Today, I'm speaking with Dr. Dan Iosifescu. Dr. Iosifescu is an Associate Professor of Psychiatry at the NYU [Grossman] School of Medicine and Director of Clinical Research at the Nathan Klein Institute for Psychiatric Research. His research has led to the validation of novel treatments for patients who have severe mood and anxiety disorders, including pharmacological treatments, such as ketamine and other glutamatergic drugs, and devices such as novel forms of magnetic simulation. Thank you so much, Dr. Iosifescu, for being with us today. Can you just tell us a little bit about the work that you have done with treatment-resistant depression over the last number of years?
[00:00:55] DR. DAN IOSIFESCU: Sure. First of all, let's just set the stage here. What is treatment-resistant depression? So there are quite a few different antidepressants currently approved and they all work, but they don't work very well in the sense that for each of them there is a relatively significant subgroup of patients that doesn't really get better even after they take that antidepressant at a good enough dose and for a long enough period of time. And one of the problems in our armamentarium, the body of treatments that we can use to treat depression, is that a lot of them are similar to each other. So essentially, they all work on the same type of monoamine receptors. So essentially, the first antidepressants were discovered by serendipity and then a lot of the following ones were trying to improve on the action of the first ones. So we end up with multiple dozens of different medications that all are somewhat in the same family—cousins or close relatives of each other. And that probably explains why there is still a very significant subgroup of patients that doesn't do well with the majority of them.
For technical purposes, we consider treatment-resistant depression to be encompassing the patients that have taken at least two antidepressants at a good enough dose for a long enough period of time and have not experienced much improvement for them. And there were these very large studies done in patients with depression. One example is the so-called STAR*D, where multiple thousands of patients were started on antidepressants and the question was what's the best sequence of treatment. And what turned out was that there was this very significant subgroup, about a third of the patients, that really didn't improve with two or more antidepressants. And that, once you're in that category, the chances of improvement with another antidepressant from the same group are relatively small. Not zero, but probably in the order of 10-12 percent. Anywhere between 1 in 10 or 1 in 6 with the majority of the patients in that group actually going through multiple, multiple treatments without finding much relief.
So that's a very bleak picture and, obviously, clinicians are trying to improve it by either using multiple medications concomitantly or combining medication with non-medication treatments, including psychotherapy, including some devices like ECT or transcranial magnetic stimulation. But at the end of the day, despite doing all these things, there's still a very significant subgroup of patients where it just does not improve. And the search has been very significant for the past several decades to try to find antidepressants with completely novel mechanisms of action, that really are not in the same ballpark as the existing antidepressants, and where one could hope that patients who don't get better with traditional antidepressants could still have a good chance of getting better with these new ones.
And my research group and others started more than 10 years ago to do studies with intravenous ketamine. And that was initially done in really small studies that were primarily crossover. So the same patient would get at one point ketamine and another point normal saline. The ketamine was administered as an intravenous infusion. And there was—because ketamine is a major anesthetic, there was a clear problem with just giving the same patients one time an anesthetic and one time just nothing and expecting them not to know the difference. Our group published the first study where a much larger number of patients was administered either ketamine or midazolam, a benzodiazepine-like drug, which mimicked some of the sedating effects of ketamine. And in that study we were actually able to replicate the already-studied effects of very solid and rapid antidepressant effects in many patients. Not everyone, but many patients. And this was helping very quickly—within 24 hours of the IV administration, which is essentially unheard of in the world of antidepressant treatments where a relatively quick effect was two to four weeks prior to those studies.
So ultimately, this was enormously exciting. And on one hand, it justified a number of additional studies looking at how exactly to administer ketamine. Some of the studies were done by my group and then others in other locations. And it turned out that, yes, you can give more a sequence of ketamine administration than just one and that is helpful. And based on that early data, Johnson & Johnson, a large pharmaceutical company, tested a small variation of ketamine, which is esketamine, an enantiomer, administered as an intranasal administration instead of IV, but it could be also done as an IV. They just decided that it's simpler to do it intranasally. And this is now already FDA approved as a drug called Spravato. And it is used probably in the same way as intravenous ketamine is as a treatment for very severe depression that has the promise of helping patients who don't get better with the standard antidepressants. And those that it does help can get improvement relatively quickly. Within days rather than weeks.
So that is all enormously exciting. It's just that when someone is terribly or sick or in an emergency room, giving them an intravenous administration of ketamine could be absolutely warranted and not a big deal. To consider this a long-term treatment becomes enormously cumbersome. So you can imagine that having to go to a doctor's office and be given an IV or intranasal administration, which can cause some short-term but significant side effects. And you need to be monitored for a few hours afterwards to just make sure that things are resolving according to the plan. And then, essentially rinse and repeat a few days later or a week later. And doing this for weeks and weeks or months and months becomes old very quickly. And the question was is there anything else that we could do to essentially have effects that are close to the effects of ketamine, which are great, but not require this cumbersome in-the-office administration, which is both expensive—because you need the person to come in to the office and be monitored for each time they take the treatment—but also, it's both expensive and logistically difficult. I mean, how can you travel? How can you be in different locations? It's really quite annoying even if it would be otherwise feasible.
So the search was on for oral medications that would have the same effects as ketamine does. Ketamine has some potent effects on a glutamate receptor called the NMDA receptor. And there were several molecules that have been proposed by different pharmaceutical companies. And unfortunately, a lot of them didn't pan out either early or later in their research cycle. And that unfortunately happens with a lot of promising drugs. One therapeutic option that we started looking into a number of years ago was an old drug called dextromethorphan. Dextromethorphan is a drug that exists in cough syrup. Maybe a lot of us have taken it while having a cold. But while it has some really interesting effects on the brain, because its metabolism is very fast, it disappears from the system very quickly and it doesn't last long enough to be showing effects on the central nervous system that would be helpful to treat any of the disorders that we're interested in.
A different pharmaceutical company paired dextromethorphan with an old cardiac drug called quinidine about 15 years ago and developed a medication used in some neurological disorders. Something called pseudobulbar affect where as a result of strokes or multiple sclerosis people have these very quick changes from laughter to crying and very dramatic changes in their mood. And it was shown to be beneficial for those patients. And we thought maybe it would be effective for depression also. And we tested this combination and found it to be possibly beneficial for depression in a very small study. The problem with that combination was that the drug that was used to prolong the effect of dextromethorphan, that drug is quinidine and it's a cardiac drug, it does have some not desirable effects on the heart and had no effect whatsoever on the brain. So the question was can we use something else to prolong the dextromethorphan metabolism that doesn't have these problems? And there are several antidepressants that could potentially do that.
There was a small company that I was working with called Axon and they picked one of these potential candidates, which is bupropion, Wellbutrin, a standard old and trusted antidepressant. But in this combination the bupropion was just there to prolong the metabolism of dextromethorphan. In fact, when we tested the antidepressant effect of the combination, one of the studies was even making sure that when you tested against bupropion alone it's still more efficacious and it was. So clearly, the prima donna in that combination is the dextromethorphan and the bupropion has an important but supporting role in prolonging the dextromethorphan metabolism and having some antidepressant effect.
And to our pleasure, this combination was shown to be a potent antidepressant. It's probably not quite as rapidly acting as ketamine is, but it's still robustly separating from placebo as early as the first week of treatment. And it is already FDA-approved and something that could be used to treat depression that has a completely new mechanism and could be just given as a prescription that people take at home. So it was a very rewarding ending to a search for the next category of antidepressants, a search that lasted more than a decade.
[00:13:26] DR. THEA GALLAGHER: Yeah, it's amazing. And you're saying this is something that psychiatrists and providers can utilize today?
[00:13:32] DR. DAN IOSIFESCU: Absolutely. And it's a drug that can be prescribed and is available in pharmacies. It's been FDA-approved since September of 2022.
[00:13:40] DR. THEA GALLAGHER: Wonderful. And when you're talking about treatment-resistant depression, is it always patients with severe depression that are treatment-resistant or can it run the range of depressive-like symptoms and levels?
[00:13:55] DR. DAN IOSIFESCU: I mean, technically, the severity is how depressed you are today. So in theory, you could be just having your first episode of depression and feel very severely depressed now, today, in this past week. The treatment resistance is also a marker of some kind of severity, but it's not necessarily that you are feeling extraordinarily depressed today, but just that your depression never gets better. And you've been depressed for a long period of time, you've tried a number of different ways to get better. Nothing worked, so it's very disheartening. But you don't necessarily have to be in the worst possible depression today. So severity is more—the way we use this term for research purposes is more a characterization of the current status of someone. Whereas “treatment-resistance” is more of a longitudinal description.
[00:14:58] DR. THEA GALLAGHER: And is there any understanding why certain people respond better to one medication versus another?
[00:15:05] DR. DAN IOSIFESCU: That's a really good question and something that we are looking a lot into. It would be really important for us to have a way to detect early on what medications would work better for what people. So there's been a lot of research done in this area. We've done some research using electroencephalograms and trying to detect patterns of brain activity that would predict which patients get better. There are studies using functional resonance magnetic imaging trying to look at the same thing. And there's even some commercially available tests that are using genetics, trying to steer treatment strategies based on some genetic factors. The net result of what we have today is really less than satisfactory. Even these commercially available tests do explain a lot about how these antidepressants are metabolized and the test would be very helpful in detecting some patterns of abnormal metabolism, which could explain why some people don't do well with certain medications. But ultimately, they don't really predict which medications are going to be most helpful for which patients.
And also, even the drugs that are not metabolized in the standard way, as long as you have that information, you could still use them and potentially use them with good effect, but just adjusting the doses. So ultimately, even that test that is commercially available is only minimally helpful and only for a small subgroup of patients which have those metabolic abnormalities. And these other tests that I was just mentioning are still works in progress. So unfortunately, well, the question you had about which factors predict which antidepressants would work is extraordinarily pertinent. We don't have a clinically useful answer at this point in time, unfortunately, despite a lot of effort.
[00:17:15] DR. THEA GALLAGHER: And that seems like where research is headed? To understand more fully who can benefit from what types of interventions?
[00:17:22] DR. DAN IOSIFESCU: Absolutely. And there is a lot of effort into either combining some of these methods of predicting antidepressant response in a more powerful aggregate predictor or, for example, refining these genetic tests in ways that would give us more insight. So I'm still very hopeful that I will have a better and more optimistic answer in five or 10 years. But unfortunately, today, or next year, I don't really expect that we would have a dramatically different answer to this, which is still that we're trying to find the best antidepressant based the patient's clinical symptoms and based on the previous history of what's been helpful or not helpful with other treatments that the person has already tried.
[00:18:17] DR. THEA GALLAGHER: I don't know if we'll use it for the podcast, but I am interested. You know, there was that study that came out a few months ago that talked about the fact that depression might not have as much of an organic cause as was previously believed, that it's more connected to life events or stressors. And I didn't know if you had a thought about how that interacts with these medications or if that changes how you think about the approach.
[00:18:40] DR. DAN IOSIFESCU: I actually wanted to clarify a bit. The study, what they did document was that—so there was this theory that depression is associated with some serotonin abnormalities in the brain and that when taking antidepressants, especially antidepressants that work on serotonin receptors, you're essentially correcting those serotonin abnormalities—be it that the receptors are abnormal or that their neurotransmitters are not secreted in adequate amounts. And that was an old theory with some variations, but ultimately—so essentially what happened was that we discovered these antidepressants essentially by serendipity. You know, there were some drugs that were tested for tuberculosis and then found to have some antidepressant effect. And then people have started using drugs that were somewhat similar. And then we reverse engineered. Well, why are these—what are these drugs actually doing? On which brain receptors are they working? Ah-ha. Then therefore, because they're working on these receptors, there must be something wrong with these receptors or with the neurotransmitters involved. And it's because of that that we have patients develop depression. And that seemed logical. It's just that it didn't pan out.
I mean, in some ways when anybody takes a serotonin reuptake inhibitor like Prozac and many other medications, their levels of serotonin in the brain would increase in a matter of hours. And yet, the antidepressant effect would only happen after weeks or months of taking that treatment. And in fact, when you use sophisticated ways of looking at brain levels of serotonin, something like positron emission tomography, you find that at the time of the clinical effect, actually, the serotonin increase in the brain is less than it was on day one where there was no antidepressant effect. So ultimately, there's a lot of data that we had even 20 years ago that was going against that theory of serotonin being critical to the antidepressant effect. The paper that you mentioned was primarily putting together a lot of the research that has been done in the more distant past and some very recently, which was completely debunking this serotonin theory of depression.
But to me, that was essentially just putting the nail in the coffin of something that we've already known that it's not really true. Essentially, most of the understanding at the neurobiological level about depression is that resilient nervous systems start making a lot more connections. And it's this spread of connections between brain cells that translates into the system being more resilient in the face of chronic stress. And that is true for depression, chronic anxiety, chronic pain, a variety of different systems. And we see this time and again. We see this with antidepressants, we see it with electric shock therapy, we see it with physical exercise. Even with ketamine, it's the story. We call it neuroplasticity, this capacity of brain cells to make new connections—this is what's really underpinning the healing and the resilience. This is also how healing looks like with psychotherapy. It's just that the majority of these studies were done with mice and we don't have very good mouse psychotherapists.
[00:22:44] DR. THEA GALLAGHER: [laughs]
[00:22:45] DR. DAN IOSIFESCU: Besides that, I'm sure that this is a common final pathway of anything that actually is associated with strong antidepressant effects. So ultimately, I don't think that the paper that you mentioned actually suggested that we don't know the biology of this process. It's just that our old understanding from 30 or 40 years ago has since been proven to not be exactly true. These SSRIs really give a major hit to the system. And that, in turn, triggers a cascade of other secondary and tertiary effects that lead to this neuroplasticity. And it's not purely the serotonin itself that's the story. And that paper was just essentially, as I said, putting the nail in the coffin to that simpler theory.
[00:23:40] DR. THEA GALLAGHER: Yeah. That's really helpful in understanding the context there. And for our listeners, prescribers, providers, people out there—we know there's a lag from research to practice. What would you advise people who are treating treatment-resistant depression patients right now? Maybe you have to reiterate what you said before, but I just want to synergize your recommendations.
[00:24:02] DR. DAN IOSIFESCU: I mean, we can apply the best of the treatments that we currently have and apply them in smart ways. And while some of the data that I was citing sounds a bit bleak, it doesn't take into account the fact that by making a good history and trying to look at the special circumstances of each individual patient, one can find solutions that are not necessarily in a standard way perhaps super helpful, but could be helpful for that one individual. So I still think that the research that I was talking about doesn't capture the role of this very sophisticated analysis of a person's history and the attempt of bringing in novel treatments. Second, there are several developments that are extraordinarily encouraging. And some of them I just mentioned with the advent of ketamine and ketamine-like drugs that are having the promise to offer meaningful help for patients who don't necessarily get better with more standard antidepressants. Other treatments have to do with novel ways of using neuromodulation. So these are devices that give energy directly to the brain.
There's an FDA-approved transcranial magnetic stimulation that has been used for a long time, but most recently there's some novel ways of delivering the TMS in a very intense protocol developed at Stanford. It's an accelerated protocol where over five days patients get a lot of TMS, 10 sessions a day for five days. But it seems to be quite helpful. There's also some other treatments that are based on, again, very novel mechanisms. In this case modulating the GABAA receptors. There's a drug called brexanolone that's been FDA-approved as an infusion for treating postpartum depression. And then some variations of that drug that are currently in phase three studies looking as potential treatments for depression in general, and they may have the advantage of not requiring long-term treatment, but just treatment for a few weeks might be helpful for some patients. And then they may not need treatment for a long period of time afterwards.
So there's a lot of development and then there's an even longer list of things that are in advanced levels of research. It's hard to talk about those because some of these may not pan out and may never actually see the light of day in clinical practice. This is, unfortunately, the normal process of trying to take exciting novel ideas and testing them. And some of them may still be exciting, but not pan out in actual use. There's one that's very dear to my heart in using a near infrared laser to try to improve the metabolism of mitochondria and brain cells, and in doing so, possibly have an antidepressant effect. We are doing two large studies here at NYU to try to test the effect in both depression and cognitive problems. The strategy is called photobiomodulation. Again, it's something that it's still in testing and cannot be really deployed clinically today, but would be extraordinarily exciting to have.
So to come back to your question, I think that there's the careful clinical approach that clinicians are using. There are these exciting novel strategies and some of them are already available in clinical practice. And then some others are very close in the pipeline and hopefully will be available relatively soon. So, on average, I think that there's no reason to be pessimistic and that there are quite a few things to look forward to.
[00:28:29] DR. THEA GALLAGHER: So it sounds like we have a number of good options and hopefully there will be even more in the future.
[00:28:35] DR. DAN IOSIFESCU: That's exactly right.
[00:28:36] DR. THEA GALLAGHER: Wonderful. Well, thank you so much for being with us and we will see you next time.
[00:28:40] DR. DAN IOSIFESCU: My real pleasure. Thank you.
[00:28:43] DR. THEA GALLAGHER: Thanks so much again, Dr. Iosifescu, for that conversation. If you enjoyed this episode, be sure to rate and subscribe to NYU Langone Insights on Psychiatry on your podcast app. On the next episode of NYU Langone Insights on Psychiatry, I'll be talking about the latest in ADHD research with Dr. Leonard Adler, Director of the Adult ADHD Program in the Department of Psychiatry at NYU Langone. For the Department of Psychiatry at NYU Langone, I'm Dr. Thea Gallagher. See you then.