NP Notes: Research and Future Directions (MDD Episode 8)

Craig Chepke, MD, DFAPA: Hello, and welcome to the Great Exchanges in Mood Disorder podcast. My name is Craig Chepke. I'm your host. I'm the scientific director of Psych Congress and the medical director of Excel Psychiatric Associates in Charlotte, North Carolina. Joining me today is my guest, Andrew Penn. Andrew, tell us a little bit about yourself.  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: Hey Craig. Nice to see you. Craig and I are also colleagues on the Psych Congress Steering Committee. I'm a psychiatric nurse practitioner by training and a clinical professor at UC San Francisco in the School of Nursing, where I divide my time between teaching psychopharmacology, practicing and teaching residents at the San Francisco VA, and doing research on rapidly acting antidepressants, including psilocybin.  

Craig Chepke, MD, DFAPA: Fantastic! So, MDD is a really hot space right now in the psychiatric landscape. It's been a lot of new advances, and as a researcher, you're part of this. What have we learned recently about neurobiology of MDD, at least some of the theories of it?  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: Well, one of the things that's been interesting that connects a lot of these rapidly acting antidepressants is neuroplasticity. And neuroplasticity is nothing new. This is something that—SSRIs cause neuroplasticity, but they take weeks and weeks to do it. And so, thinking about different mechanisms which allow for perhaps neuroplasticity or any kind of rapidly acting antidepressant response is advantageous because—I always think about antibiotics, right? If I was told that I had an infection, and it might take four-to-six weeks for this medication to start to make me feel better, and we might need to try two or three different ones before we get that right, and you'll have an infection the whole time. I would be kind of underwhelmed by that offering. But that's kind of been standard of practice in psychiatry, biological psychiatry, for 50-plus years now.  

Craig Chepke, MD, DFAPA: Yeah, I mean, I've never said it to a patient this way, but for educational purposes, I'll kind of only slightly exaggerate it to say, more or less what we tell people is, I know that you're at the end of your rope. You might feel like life isn't worth living and this medication, best-case scenario, you'll feel absolutely nothing for a month. If you feel anything, it's going to be a side effect. So I'm hoping you get no effects from it whatsoever for a month, and then maybe you'll start to feel a little bit better. That's not a great value proposition, unfortunately.   

Andrew Penn, RN, MS, NP, CNS, APRN-BC: No, it's not. And it really underscores why we've needed these rapidly acting antidepressants for a long time, and fortunately, we’re increasingly…we're seeing more research into this area. I think ketamine—a dozen or more now. I mean, the rapidly acting effects of ketamine were, I think, stumbled across by Robert Berman in what, 1999? So we're now a quarter century into that discovery. And of course, ketamine has really led the pack in a lot of ways. And then esketamine, a few years ago, got approval, initially as an adjunct treatment and now more recently as a monotherapy. And these are both treatments that have the potential to improve somebody's mood within a few hours to a day or so, which is exciting.

I mean, that's really exciting to have the opportunity to do that. And there's a lot, those are obviously glutamatergic agents, but there are other mechanisms of action that are being explored. So what I'm working on with psilocybin, psilocybin is a serotonin 2A agonist and also appears to have a rapidly acting antidepressant effect. It's one of a number of different psychedelics, some of which are sort of known like psilocybin, but also things that are maybe a little more esoteric, such as dimethyltryptamine or 5-methoxy-dimethyltryptamine, 5-MeO-DMT, both of which are being looked at as rapidly acting antidepressant treatments. And then interesting things like the use botulinum toxin-A, Botox, as a way of changing emotional proprioception, I think it's been called.  

When we walk around, when we have depression, with this sort of frown on our face, that our brain gets the message that something's wrong and responds in kind. And so by disrupting that pathway, you can have this rapidly acting antidepressant response. So just the idea that not settling for this idea that you have to continue to feel lousy for weeks and weeks before you might get some response. I think it's really asking our field to expect better. And I think that alone is really exciting. I feel more energized. I've been working in psychiatry in some form or another for over 30 years, and so I'm probably more excited at this point in my career than I have at any time in the past in terms of where research is going and what the future might hold.  

Craig Chepke, MD, DFAPA: Yeah, I completely agree with you. I think that as a field we had lowered our expectations that the treatments, yes, there has been an evolution, but it's been a long slow crawl. The slope of it, of the improvement has been very minimal. Outcomes are not dramatically better with newer antidepressants up until very recently when we started to get new mechanisms of action, but that we just kind of figured, well, this is the best we can get. So as my wife says to our kids, are you being grateful or ungrateful? I didn't want to be ungrateful. We're getting some better treatments, but really we need to raise our bar for what we expect because patients do deserve a heck of a lot better, in my opinion.  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: They do. And the fact that, not to get too discouraging about this, but to think that we've had all of this advancement in psychiatry, but yet some of our final end outcomes like our suicide rate have not gone down. If anything, they've gone up. And that's obviously a complicated, there's complicated reasons for that. We've gone through a pandemic and there's a much greater appreciation that mental health is not a luxury, and absolutely it's as much an important part of your healthcare as your heart or your lungs. And so there's a lot of reasons for that, but it really points to the need that we've got to do better. And I think these treatments that we're working on will eventually, some of them will fail. That's just the nature of research. Things drop off, but hopefully the cream will rise to the top.  

Craig Chepke, MD, DFAPA: Right. Now, you said something earlier that piqued my interest. I was hoping you could clarify that for me and for the audience. So, psilocybin is a serotonin 2A agonist, but serotonin 2A antagonism as part of atypical antipsychotics or otherwise is associated with antidepressant response as well. So how can serotonin 2A agonism be antidepressant if serotonin 2A antagonism is antidepressant?  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: It's a really interesting question. I don't think we fully understand the answer to that. We do know that if you block serotonin 2A in animal models, they use something called ketanserin, which is a serotonin 2A antagonist. But even in all of our studies, we need to make sure that people are not taking serotonin 2A antagonists, even something as pedestrian as trazodone, in the days leading up to their session because those will definitely blunt, at least the subjective effects and presumably the antidepressant effects, of psilocybin. But it is something that is usually taken off to make sure that the psilocybin has a receptor to attach to.  

Craig Chepke, MD, DFAPA: Yeah, I think of it in a couple of different ways. One is that people are wired differently. In some people, their depression—cause, I mean, MDD as a construct is kind of a garbage fire. I mean, there's 227 different combinations by most people's math that you can have of symptoms and get the same diagnosis with MDD. That's a lot of different illnesses balled up into one. Some of those people, serotonin 2A agonism might be the right way to go. Some others, they have a different underlying illness that we still call MDD, that antagonism works better. And then on a more granular level, we assume that if you stimulate a receptor, only one thing's going to happen. If you block it, only one thing's going to happen. The two most common answers I give are it depends, and it's more complicated than that.  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: That's right.  

Craig Chepke, MD, DFAPA: Not that my wife nor my patients like those answers, but that's just how it is. And sometimes certain agonists can do different things. We call them biased ligands that it will bias it to one pathway versus another. And then same thing, antagonism. And you can have different results binding at the same receptor.  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: And also the difference between chronic stimulation or blockage of a receptor versus episodic.  And so, there's a lot of side effects from psilocybin that you wouldn't want to have every day. It can be a pretty tense experience. It's not an experience that you could go to work having. So, in the same way that, well, neither is general anesthesia. Very effective if you need to have surgery, but you don't want to go to work on general anesthesia, obviously. And so, there's that question, too, of when we activate a receptor briefly versus activating it chronically, and of course the chronic stimulation of or blockage of receptors is what leads to not only side effects, but also then perturbation of homeostatic systems.  

Craig Chepke, MD, DFAPA: Exactly. Up-regulation, downregulation.

Andrew Penn, RN, MS, NP, CNS, APRN-BC: The system adjusts to that shift. And so, the nice thing about the rapidly acting treatments is you kind of get in, make the change, get out, and you don't keep tickling that receptor chronically. And so by doing that, you can reduce a lot of the side effects that come with that kind of chronic stimulation of a receptor.  

Craig Chepke, MD, DFAPA: Yeah. I want to drill down on that a little bit because the rapid-acting antidepressant that I have the most experience with is esketamine. I have a treatment center at my office, and when I talk to patients about the potential adverse effects and I show them the chart and everything, and they look at some of the percentages and they think, ‘Oh my God, why would I want to take this?’ And I tell them that, well, what you have to consider is that you're thinking about side—and honestly, I say this as much to fellow clinicians conditioned to this as well, we're conditioned that all of our treatments are daily oral medications. And that a side effect that you see is something you're going to get every day if you take the medication every day, but you don't take this every day. You take it three times a week for the first month—you take it twice a week for the first month—and then you take it for once a week and then go down from there. And because it's got a short half-life, it's only in your system for an hour and a half, two hours, that you're probably getting the side effects. And then they're usually gone.  

And so you're only getting side effects for a few hours a week instead of for every day of the week. And then I always see light bulbs go off like, ‘Oh!’ and they never thought about that. And many patients have told me that they feel that esketamine is better tolerated than oral antidepressants have been, even though the list, when you look at it at face value looks more daunting, they're a completely different ballgame.  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: Well, let me challenge you one step further with that and say, rather than just thinking of those things as enduring a side effect, and depending on how you phrase it, so dissociation or anxiety, those sound unpleasant. But what if we frame that and we said for an hour and a half, maybe an hour, hour and a half, we're going to quiet down that rumination chatter, that stick that you beat yourself with all day long about what a rotten person you are. What if we turn the volume down on that for an hour? Now you and I might call that disassociation, or I used to kind of tease the Spravato folks, ‘Why are you calling the psychedelic effects a side effect?’ What if we saw those as an opportunity? Because what we invite people to do in our studies is to really actually surrender into that, to not resist those—what might be called side effects, those kind of strange symptoms of it—but rather to think of that as an opportunity to step away from your usual way of thinking about things, that maybe isn't working so well for you you wouldn't probably be in this study, right? That maybe you wouldn’t have—the depression is a symptom of…the depression comes along with this kind of rumination and inability to shift your thinking, right?  

And so, what if for a few minutes, or an hour, or a better part of a day in my case with psilocybin cause it tends to last about four or five hours, is that you just have a break from that and maybe can see things from a slightly different angle. And yeah, you might feel a little weird, just like if you got to have a colonoscopy and you're going to have midazolam and fentanyl, you're going to feel a little weird for a little while, but you don't really want to be awake for that anyway. So it's a gift in the same way. So thinking of it differently rather than, like you said, this is something you would have to deal with every day, that this is something that is temporary and maybe not even adverse, maybe has some salutatory properties. And unfortunately, because we have so a little nuance in our vocabulary around drug effects, a lot of people associate that with just getting high. I remember talking about ketamine to a group of psychiatrists back in 2012, and one of them sort of dismissively said, ‘Well, of course you felt better. You got them high.”  

And I said, ‘Well, you and I both know the half-life of ketamine is short, so why did they feel less depressed four days later?’ You're not still intoxicated from the ketamine, so clearly there's something else going on here. And some of that may be neurogenesis, and that may be that unleashing mTOR pathways and BDNF and all that, but it may also be the psychological experience of just getting a rest for a brief moment from this kind of relentless rumination that a lot of patients tell us that they have that makes it miserable.  

Craig Chepke, MD, DFAPA: Yeah, absolutely. There's debates that you're far more informed about than I am about is the psychedelic dissociative experience necessary for efficacy with these type of rapid-acting treatments? What are your thoughts on that?  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: Yeah. Well, this is a big question, right? Because obviously, having to create safe spaces, and even with a ketamine clinic or esketamine clinic, you still have to have a place under the REMS to have people, to park people for a couple hours where it's quiet and pleasant and hopefully not too noisy. So, there are those administration challenges that if this was just something that you could take on your own, it's a lot easier to kind of slot into our existing system of, at least, biological psychiatry. I mean, therapists are used to spending an hour with their patients, but a lot of us medication prescribers are not.

And so the idea of being there for an hour or two, which is why there's probably also an interest in some of these shorter-acting psychedelics, like 5-MeO-DMT, is that, or esketamine also has a similar—racemic ketamine—where you can book a two-hour slot of time and get the person in and out of your office. Whereas psilocybin, it's an all-day affair, not very practical in our current healthcare system. But yeah, this question of the subjective psychedelic experience, there are a number of commercial entities that are looking at this. I think it's just really not known at this point. We're still trying to understand how much of the context determines the outcome. So if somebody has a psychedelic experience in a very enriched environment where there's a caring therapist there and it's a nicely comfortable space, does that change the outcome, or does that add additional value to the treatment?  

How much psychotherapy do you need with this? I mean, this is another big open question, an important one because it has big workforce implications and health cost benefits or health cost implications. But if we get people better and they don't need as much treatment over chronic treatment, do we end up saving in the end? And these are all big open questions for debate and important ones, and there are things we shouldn't—our friend, Chuck Raison always likes to say, I think his mentor used to say to him, if you don't want to follow the evidence, you probably shouldn't be in science, right?  

Craig Chepke, MD, DFAPA: Yeah.

Andrew Penn, RN, MS, NP, CNS, APRN-BC: And so there are a lot of arguments that are quite—said with great conviction in the psychedelic space around the importance of these things, but many of them are not actually proven, or they're not shown in a head-to-head kind of model. It definitely seems that that relationship and that care, all that really matters. But we really need to do some studies where one group of people gets that really enriched environment and the other people get a very minimal kind of environment and see what the difference is, if there is one.

Craig Chepke, MD, DFAPA: So many unanswered questions. And unfortunately, we're out of time to try to explore them. I want to thank you so much for being with me today, Andrew.  

Andrew Penn, RN, MS, NP, CNS, APRN-BC: Thanks for having me, Craig. Nice to see you.  

Craig Chepke, MD, DFAPA: And thanks to everyone for joining us today on the Great Exchanges in Mood Disorders podcast.