This transcript has been edited for clarity.
Stephen M. Strakowski, MD: Hello. Thank you so much for joining us today. I'm very excited to have two very illustrious and intelligent guests talk us through an interesting topic, the use of ketamine for depression.
I'm Dr Stephen Strakowski, a professor of psychiatry at both Indiana University and the Dell Medical School at the University of Texas at Austin. With me, I have Dr Gerard Sanacora, professor of psychiatry and director of the Yale Depression Research Program at Yale School of Medicine, and Dr Charles Nemeroff, professor and chair at the Dell Medical School at the University of Texas at Austin. Welcome, gentlemen.
To me, at least, ketamine seems to have hit the scene and been adopted pretty quickly for the treatment of depression, after years of watching things slowly develop. Gerry, where are we with ketamine in the treatment of depression? What do we know about it at this point?
Too Soon, or Right on Time?
Gerard Sanacora, MD, PhD: I'm not sure I'd agree with your perception that it hit the scene pretty quickly. The first publication was back in 2000, so it's been about a 20-year trajectory. Hopefully that's not quick in our field. But I do think the rate of growth has increased dramatically since the US Food and Drug Administration (FDA) approved of esketamine back in 2019.
We actually know quite a bit about ketamine, more than we do with many treatments that we use. There are now large long-term studies, at least with esketamine, that have been published. There's more and more real-world data being published with IV use of racemic ketamine. So I think that we know more than we may be willing to say about both the pros and the cons of it at this point.
Strakowski: Charlie, what are your thoughts on this?
Charles B. Nemeroff, MD, PhD: Not surprisingly, I disagree with Gerry. First, the original pilot study had so few patients, and then there was a tremendous gap, so that really does make this a relatively recent development.
There are 517 ketamine clinics in the United States today. To say it's worrisome would be putting it mildly. Gerry and I worked on a consensus statement on the use of ketamine in the treatment of depression that was published in JAMA Psychiatry. I would hazard a guess that of those 517 ketamine clinics, less than 5% adhere to the standards that we espoused in that paper related to the workup of patients, safety issues, etc. So, I'm very concerned about where the state of ketamine is in the United States today.
Strakowski: Gerry, have you also seen that people are taking short cuts with the guidelines?
Sanacora: I'll back up a little bit. I don't think Charlie was disagreeing, really. We weren't saying two opposite things. You asked me what we know about ketamine, and I presented what we know. How it's being put into practice may be a little bit different. On that topic, we probably agree more.
There are some major gaps. We now have a lot of information on the efficacy and the safety. The data are there. We have pretty large samples. It would be much better if we had a registry that we could use to get ongoing real-world data.
The real concern is when people are practicing outside of the guidelines and outside of what has been done in these randomized controlled trials and long-term follow-up trials with esketamine. The further we get away from that, the more risk we're putting patients at.
Two Takes on Evidence of Ketamine's Efficacy
Strakowski: Charlie, what do we know about efficacy of ketamine and the knowledge gaps that can help us properly place this treatment among what we prescribe?
Nemeroff: I'm much less impressed with the magnitude of the efficacy data than Gerry is. The FDA package for esketamine was very weak. A number of investigators have raised the question of whether it actually should have been approved. The geriatric trial completely failed. That left two trials, an acute trial and a relapse-prevention trial.
In the acute trial that was published in The American Journal of Psychiatry by Popova and colleagues, there were serious problems with those data. Men didn't separate at all between esketamine and placebo, and neither did individuals with less than three episodes of treatment resistance or 18- to 44-year-olds. That was one of the pivotal studies. There were equal number of problems with the relapse-prevention data. In fact, Turner wrote an article in Lancet Psychiatry raising questions about whether the package should have been actually approved.
We also have to remember that all the intravenous (IV) ketamine data are of off-label use. I'm not convinced, either clinically or otherwise, of the magnitude or the sustainability of the effect.
Strakowski: Gerry, what do you think about that?
Sanacora: I'd respond by noting the pooled data, such as the meta-analysis by Papakostas and colleagues, who looked at the five pooled randomized controlled trials with esketamine, that had 774 patients. There were pretty clear differences, both statistically and clinically, in terms of total change and also in response and remission rates.
The most important thing to realize is that people are getting confused between what type of effect size you'd expect to see in these studies vs standard antidepressants. This is actually on top of a new treatment. So you're actually comparing this to a new selective serotonin reuptake inhibitor (SSRI) or a new serotonin-norepinephrine reuptake inhibitor (SNRI). That's not typically how we look at outcome studies.
Strakowski: Do you feel like that adds a little more heft to the findings?
Sanacora: I definitely think so. You're not comparing it to placebo. You're comparing it to a new newly started SSRI or SNRI, at least for the treatment-resistant studies.
Strakowski: Charlie, I've wondered about something you mentioned, which is whether the IV preparation is perhaps superior to the nasal preparation. Could that have contributed to part of the confusion around this? It's probably not been compared in a head-to-head study.
Nemeroff: There are a few things about the data. You know the kinds of patients we see here in our treatment-resistant depression program, Steve. We have only had to send a very small percentage of patients to ketamine because other FDA-approved treatments get them into remission.
So my concern about the ketamine clinics that have sprung up is that the patients who go there have not had evidence-based psychotherapy or other prior pharmacotherapies. That raises the question: Where does it fit in the algorithm?
Where Ketamine Fits in the Treatment Algorithm
Strakowski: Where would each of you put it in your algorithm, in terms of who gets it, when, and where it fits in.
Sanacora: Charlie, I agree with you that there is a real concern of leapfrogging other treatments without good cause. In our interventional psychiatry service, the large majority of people we see have failed at least four treatments. Probably about half have tried electroconvulsive therapy (ECT) and either find it intolerable or are not able to use it. This is a group I think you can clearly argue for using ketamine.
As you scale back from that, there are two large studies underway. One is the study sponsored by the Patient-Centered Outcomes Research Institute that we're part of, which is a direct head-to-head comparison between ECT and ketamine. There's also the Canadian group looking at a very similar study. We'll get an answer to that soon.
But the FDA approval at least is for treatment-resistant depression, which is having failed two treatments. That really should be a minimum. Those data really suggest that the people that had failed more treatments actually separated better and did better. So it really is for more severely treatment-resistant patients. Where exactly we put it in the algorithm is an individual decision based on the patient.
Strakowski: But Gerry, in that protocol, unfortunately, one of the two treatments that was considered to fulfill the criteria of a failure was an antipsychotic augmentation. They didn't really have two full-scale antidepressant treatment failures.
Sanacora: Exactly. But again, the people that had the more severe failure actually look like they did better in separating. So we're arguing for the same thing in a way, that this is not something that I would try first-line unless there was a real serious reason to do it, like acute suicidality or some other reason where you needed to get somebody better quickly. The important thing is to have a long-term plan on how to maintain that.
Seeking Clarity Around Ketamine's Method Action
Nemeroff: I don't think Gerry and I disagree very much. My remaining issues have to do with, number one, the obvious lack of blinding, which you just can't get away from. It's the same issue with psychedelics.
Secondly, there are issues around the mechanism of action. You can't get away from the fact that naltrexone completely blocks ketamine's antidepressant effects. We need to be upfront about it and say this is likely an opiate mechanism. I'm not saying that's a bad thing necessarily, but we need to be upfront about it.
Sanacora: Charlie, I would disagree on two things. The Stanford study that showed that was very small. To extrapolate too much from that, I think, is risky. It really didn't completely block it, but definitely attenuated the effect. But the opiate system also seems to be critical just in simple placebo response. You can block a lot of the placebo effects of pain and now even some evidence of mood.
I don't think we know that placebo is directly activating the opiate system. It may involve endogenous stimulation of the opiate system, which I don't doubt but I don't think the evidence is very strong that ketamine itself is directly binding to the opiate receptor and generating the effect that way.
Nemeroff: We need to consider if it's causing the release of endogenous opiates, which it likely is. In the paper published in Molecular Psychiatry, ketamine's antisuicide effect was completely abolished by naltrexone pretreatment. As you know, Dr Alan Schatzberg is in the middle of a study funded by the American Foundation for Suicide Prevention. So we'll get more data there.
Sanacora: We can agree we need more data. At least, I feel we need more data. It's very intriguing, and I don't doubt that the opioid system is involved. But like I said, using naltrexone can do a pretty good job of blocking placebo response.
Nemeroff: A study that would be of great interest would be to directly compare ketamine with an opiate in the treatment of resistant depression. Then we can get an answer, or baring that, even with a stimulant.
Sanacora: Along with that, or maybe even before that, we also need a head-to-head comparison of ECT, which we're going to see. Even a comparison with a second-generation antipsychotic would be really interesting to see.
But to get at the mechanism, it's complicated. I doubt very much that there is a single mechanism involved in this effect. I can't think of really any medicine where there is a single mechanism. So I don't doubt that the opiate system is involved in some way, but I just don't think it's direct. I'm not sure that we could justify the ethics of doing an opiate study just to answer that question.
Strakowski: You got ahead of me and answered my question. It sounds like we have some thoughts of where the mechanism or mechanisms may be, but we don't really understand how this drug works. Is that fair?
Nemeroff: Wouldn't you say, Gerry, that if it acts partly through an opiate mechanism, then issues that relate to tachyphylaxis over repeated use or even withdrawal need to be considered?
Sanacora: Whether or not it acts through an opiate system, we have to consider those. We know that ketamine is a drug that is abused. We don't have to worry about the mechanism so much. We know that people will misuse ketamine. So that's a concern for me, regardless of the mechanism. I agree with you there.
I'm just less convinced that it truly is has the addictive quality of an opiate. At least, I personally haven't seen any of the rapid withdrawal symptoms that we would typically see with opiates.
Lack of Standardization Is Hurting Our Understanding of Ketamine's Safety
Strakowski: Do we have enough postmarket surveillance yet to really know if we're having that as a problem?
Sanacora: I would argue that we definitely could use more. We have that ability with esketamine but, unfortunately, a large percentage of the treatments being used are not with esketamine and aren't following the dosing guidelines or the frequency. So I really do think we need closer surveillance, not just postmarket with esketamine, but some way of getting a registry involved in ketamine treatments.
Nemeroff: Gerry's point is really well taken. What's really concerning to me is the number of clinics that will literally put on their website the fact that they are delivering ketamine at doses up to 2 mg/kg and are willing to give it twice a day. This is really concerning.
Strakowski: It is. My impression is most of those are using IV preparation as the primary driver. I know of emergency rooms, as I'm sure you do as well, where they were starting to use it for acutely suicidal people, with virtually no guidance support. We can all agree that that's premature.
That gets back to my original impression that this has come on so fast and is maybe getting a little bit ahead of itself from a data perspective.
Nemeroff: Coming over to Gerry's side here for a minute, I will say though that what the ketamine experience has shown us is that the brain is capable of responding in a rapid fashion. That's really exciting.
Strakowski: It is.
Sanacora: Maybe one of the biggest areas to look at is how the whole experience with ketamine has changed our perspective of both the pathophysiology underlying depression and also the recovery.
Up to 20 years ago, it just was unheard of — maybe with the exception of sleep deprivation for a few hours — improving depression. But this idea that we can have a rapid improvement is pretty impressive. The ketamine studies really do seem to show a sustained improvement with continued dosing. It's just really how do you manage that long term that, for me, is the biggest question.
Strakowski: It may be a really important first step in the next phase of how we move the treatment of depression forward. The psychedelics are kind of entering that too. I don't want to get into that in great detail, but they share a lot in common with this experience, correct?
Sanacora: It has a real profound, immediate effect on patients' perceptions and cognitions that may play a real large role in the clinical benefit.
Nemeroff: The exception is the publication in Nature Medicine looking at MDMA in posttraumatic stress disorder (PTSD). Comparatively, the published psilocybin data have a much smaller magnitude of an effect. Also, the total number of patients that have been entered into randomized clinical trials with psilocybin to date in terms of the published literature is under 250, and that's across all indications, not just depression, but alcohol, tobacco, PTSD, etc. So if you want to talk about a really meager database...
Strakowski: The other thing reminds me of is that, to date, we have what we have in depression with ketamine but we really don't know much about its use in other conditions. I don't think it's entered those treatment algorithms yet outside depression. Is that fair?
Nemeroff: There was research in PTSD that came out of the Mt Sinai group that were randomized controlled trials, such as they can be, that were positive with ketamine.
Sanacora: There's mixed results, but leaning toward the positive, with obsessive-compulsive disorder also. Real-world data, lead in part by Rosenblat and McIntyre, suggest that it may go just beyond unipolar depression. However, the quality of the data definitely drops off quickly the further you get away from treatment-resistant depression and next-day suicidal ideation.
Strakowski: It's really premature to recommend it otherwise at this point.
A Consensus on What's Needed Next
Strakowski: To summarize, it sounds like at this point in our data experience, this really is still an option best suited for treatment-resistant depression, fairly vigorously defined. Then we're all a little bit skeptical of clinics popping up and potentially marketing it for first-line use. Is that fair?
Nemeroff: Yes. One of the things that Gerry and I are in 100% alignment with is how remarkable it is that no regulatory body has stepped in to consider how to manage these clinics. You would think the local medical societies might be involved, the state medical boards. The vast majority of these clinics aren't run by psychiatrists.
Yet, no one has stepped up, including the FDA, because it's off-label. We called for that in our report. Fundamentally, it was a plea to have someone step forward and say, "You need to manage this."
Honestly, let's say we all decided we were going to open a neurosurgery clinic at the mall. We're all licensed to practice medicine. But, I would imagine we would be investigated relatively quickly.
Strakowski: I hope. I certainly wouldn't refer anyone to us.
Nemeroff: Why has this been allowed to continue?
Sanacora: I would say two things. One, the unintended consequences of what has happened from the FDA placing pretty rigorous Risk Evaluation and Mitigation Strategies (REMS) on esketamine, has been this shift to moving to the use of the nonapproved version, which is racemic ketamine, because it doesn't have those restrictions. I don't think that was the intended consequences of the FDA choosing to put the REMs on, but it really has been the result of it. I think that has had a big effect.
As Charlie noted, many people running these clinics aren't psychiatrists. I'm a little mixed on that. I don't know if you need to be a psychiatrist to provide ketamine treatment, as long as you realize this is just a small part of the treatment plan. This is not a miracle drug. It's not as if you give somebody one dose — or even eight or ten doses — and it's a miracle cure. This is part of the treatment plan. If your depression is severe enough to require this type of treatment, you require close psychiatric care in some way. At least, that's my opinion on that.
Strakowski: That's a great final statement. Gentlemen, we mostly agree, I think. I appreciate that.
We're at a point with this drug where it's exciting. There's a potential to see something really different in how we approach depression. But we do have to watch ourselves so we don't let our enthusiasm for the novel get ahead of the data. At times, we run that risk.
Gerry and Charlie, thank you very much for your time today. I appreciate it. This will be useful to people who read it and watch this. Thank you all for tuning into us.
This Stephen Strakowski. Goodbye.