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New Classes of Treatment for MDD


Experts provide an overview of novel treatments, including glutamatergic, GABAergic, and psychedelic drugs, that are either approved or currently being evaluated in clinical studies for MDD (major depressive disorders).

Greg Mattingly, MD: Let's dive into some of the classes of new medicines that are on horizon now. We've talked about it upfront, we've mentioned a few of these, but it's an exciting time. I've done this for 30 years and there are more new mechanisms being developed right now than at any time in my 30-year career. Just recently, at one of our recent congress meetings, I did a talk about research and clinical practice, and I said, “How many new mechanisms are currently in development?” Just ones that I'm currently in trials with, Jeremy. It was 14, 14 novel mechanisms that hit the brain differently than what we have. If we think about some of those novel mechanisms, it would be glutamate-type mechanisms that hit the NMDA [N-methyl-D-aspartate] and the AMPA receptors and the cascade under glutamate, it would be the GABAergictreatment [gamma-aminobutyric acid]options, which would be primarily the neural steroids, which modulate those intrasynaptic, but extrasynaptic GABA receptors. Then it would be the psychedelics, which modulate serotonin 2A. Those are some of the 3 really exciting kind of areas of research right now when it comes to depression. When you think about glutamate, GABA, and psychedelics, I know you're a clinician, not as much of a researcher as I tend to be sometimes, but what do you think of when you hear, glutamate, GABA, and psychedelics? Is it exciting, is it not exciting? Is it overwhelming? How do we convey this new language to our patients?

Jeremy Schreiber, MSN, PMHNP-BC: It's fascinating, is what I think it is. We have some treatments that work on glutamine in the NMDA receptor. I use these treatments in my practice currently and I've seen patients that have had been unemployed that have gone to working and been out of the hospital for months and months and months. It's life-changing in terms of the extrasynaptic GABA receptors. This is also something that is going to be quite remarkable. Specifically, when I think about glutamate and GABA, I think about the balance between these 2 systems. If we think about the neurotransmitters we have, the monoamines that we regulate right now, we're looking at the primary excitatory neurotransmitter, the primary inhibitory neurotransmitter. All of this being said, I think we have to look at what I would call the balance between the 2 systems and regulating that balance appropriately. I'm very fascinated with the utilization of psychedelics as well. I was on my lunch and I was starting to look [into], how does microdosing work? Where can this even be had, and it's Denver, you can have some of the psilocybin stuff in Denver. I think it would be great for some of my patients, but I, at this point, I don't even know where I can go to recommend my patients get these types of treatments or if they would have to travel across the country. Right now, we have limited access to some of the psychedelic treatments, but I have a high degree of suspicion that these are going to be remarkable. I'm also very excited to think that these products will become available in the marketplace in the near future. And I'm happy that we're actually researching them as opposed to leaving them out there where we're not even allowed to evaluate these products because of the [attitude that they’re] potentially dangerous. That's been a detriment, honestly, quite frankly, to medical science for a lot of years.

Greg Mattingly, MD: I'll just walk the audience through the different mechanisms. We have the glutamate magnets, as you talked about, that involve glutamate as the main excitatory chemical in the brain. It makes nerve cells fire and it turns on neuroplasticity. We have the GABAergic treatments, these neural steroids that are coming down the road. We have one that's FDA-approved. We have another one that's in development. The exciting part is that's the main brake in the gas system. So it's the gas pedal and the brake, it controls neural networks, it sets neural tone, it tends to enhance neuroplasticity. Finally, we have the psychedelics, which have been shown to enhance neuroplasticity. All 3 of these mechanisms have the hope of being rapid acting. You don't have to wait weeks to months. They all seem to work within hours to days. Three different mechanisms that all have rapid onset. The reason I'm really excited, Jeremy, is neuroplasticity. Helping neural networks that have been damaged over time by having depression, having childhood trauma, having excessive stress, but turning on neuroplasticity. Let me walk the audience [through] where we are right now as far as FDA-approved. So in the glutamate system, we have an intranasal version, which is approved. You start out twice a week [with] esketamine, and then after 4 weeks, you start spacing it out. We have a newly approved oral version. It's a combination of bupropion plus dextromethorphan. You start out once a day for the first 3 days, then you go to once, twice a day. That's our first oral glutamate-targeted compound. The GABAergic system, if we're thinking about those medicines that don't just hit the synapse, which is what benzodiazepines do, but they hit the extrasynaptic site that resets neural tone. It's a different GABA receptor subtype there. These neural steroids, we have one that is IV-approved for a postpartum depression. The negative there is it takes a long IV infusion, but it tends to break depression after 60 hours. We have one in development that I've been a part of research with that you take it once a day for 2 weeks, and then you only take it again as needed. That data has been really exciting. I just presented a poster at the APA [American Psychological Association] with Zuranolone and we used the PHQ-9 to measure, “Do people start having signs of a relapse?”Psychedelics, none that are yet FDA-approved, a couple of companies are doing them in conjunction with psychotherapy. The interesting part there is if I combine one of these rapid-acting medicines that's neurally plastic, has it helped to benefit by encouraging psychotherapy at the same time? My hunch is it does. My hunch is [that] with all of these rapid-acting medicines, it does. I think encouraging psychotherapy in the context of using these rapid-acting medicines that are increasing neuroplasticity, I think adding psychotherapy at the same time, is going to be a really exciting component of it.

Jeremy Schreiber, MSN, PMHNP-BC: That plays into your point earlier about talking to patients and instilling hope in these sorts of things. I talked about the time constraints. I have my visits set up with my patients that they're at least 30 minutes, at least 30 minutes. I try to do psychotherapy frequently with all of my patients. I think that it gives us good benefits. We also know from the research that, antidepressant medications or standard-of-care antidepressants, we get this result and psychotherapy, we get this result, but it's not necessarily a 1-plus-1 equals2. It's a synergistic response. I think that we will see increased synergism with these newer agents as well because of that neuroplasticity.

Greg Mattingly, MD: What do you think about, and this is something I was just thinking as we're talking, this new group of medicines that have faster onset, that have different mechanisms that are inducing neuroplasticity. What do you think about their chance of breaking down stigma when it comes to depression and brain health?

Jeremy Schreiber, MSN, PMHNP-BC: That's a really good question. I think that it certainly can help reduce some of the stigma because it will allow depression to become more mainstream, or more so than it is currently. I still talk to patients who tell me things like, "Oh, my family doesn't believe in mental illness and these sorts of things." However, with rapid-acting treatments and with the ability to get our patients resolved much more quickly, I think there will be a lot more of a push out there in the mass media as well. With that being said, with a bigger push, it will lead to more education and a decreased stigma.

Greg Mattingly, MD: I think it's going to lead to more awareness. I think it's going to lead to more awareness, which will help to break down stigma. It's OK to come and ask for help. We have treatment that can move the needle in a course of days to weeks instead of months to years of chronic treatment, maybe the rest of your life of chronic treatment. Is there any pitfall with these rapid-acting medicines? The big thing there is, we put you on something, it gets you better, but how do we make sure that you don't start to have a recurrence or the next episode? What do we need to be careful of there?

Jeremy Schreiber, MSN, PMHNP-BC: That's a great question and I'm going to turn that back to you first and let you go with the first answer while I collect my thoughts a little bit.

Greg Mattingly, MD: One of the trials I've been a part of, and I think this is the way we're going to move in the future, is I told you we gave the people to PHQ-9, we let them go home. If that PHQ-9 triggered over a 10,we called patients, we made sure they were OK, and we said, “We need to bring you back in.” It was almost like having a thermometer at home. If I start to have a fever and I'm managing somebody who has a history of bronchitis, they can call me and say, "Hey, listen, I popped a fever." “Well, let's talk about what temperature it is.”“Well, it's 99.5 [°F].”“Well, take some ibuprofen. Call me tomorrow if you're not ok.” "Hey, it's 102 [°F] and a half." Different discussion. “Let's get you in. Let's see how you're doing, let's get you back on something.”These intermittent treatments, in some ways they're going to make us be better clinicians. They're going to make us look for, do we see the early signs of somebody starting to have a decompensation? In the same way, a good cancer doctor, Jeremy, they don't say, "Hey, I've treated your cancer. Call me if you have problems." What do they do? They measure for relapse. They look to see if there's any tumor recurrence, they track your PSA. We're going to do the same thing with some of these new treatment models. It's really exciting about moving the field forward when we talk about outcomes for our patients.

Jeremy Schreiber, MSN, PMHNP-BC: That's what we're looking for is good outcomes for our patients.


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