Examining New Agents for MDD Treatment (AXS-05)


Clinicians begin their review of three new agents approved for the treatment of major depressive disorder (MDD).


Gus Alva, MD, DFAPA: With that in mind, what I’d like [us] to think about is maybe taking into consideration 3 relatively newer agents that we have at our disposal right now. Because what I’d like to do is maybe have you [all] ponder the point of time-to-treatment response and trial data that you’ve been impressed with, 3 things. The first one is the combination of dextromethorphan with bupropion, or AXS-05. That’s a latest medicine that got FDA approved for major depressive disorder. I also want you to take into consideration zuranolone, a neurosteroid. Again, following all the heels of brexanolone, but now the oral option to that IV [intravenous] intervention that we had before with just brexanolone. And then lastly, some musings on esketamine, which is given [as] an intranasal; [the] difference there, treatment-resistant depression. So, again, major depressive disorder, postpartum depression, treatment-resistant depression. But if you wouldn’t mind sharing with us the data that you feel is most compelling and most useful for clinicians at the present time regarding each one of these particular modalities.

Greg Mattingly, MD: I’ll say the one that’s been the biggest surprise for me has been that combination of bupropion and dextromethorphan. Gus, [I think] you and I were in the trials. I did the trials, trials look good. It got breakthrough status by the FDA. That doesn’t happen very often. But even then, I’ll have to say my clinical experience has been even above that. So I’ve seen that be transformative for a number of the patients in my practice. Once again, bupropion’s raising the dextromethorphan level to get glutamate stimulation, to get sigma opioid receptor stimulation, which gets involved with inflammation. And that combination was shown to have very fast onset, and to have something that Erin touched on, it improved anhedonia. So not only [is it] getting my depression better, but [it’s making] my sense of joy better. I’ve seen that over and over again in my clinical practice. When that medicine’s effective, it’s not only helped depression, it’s also helped restore the joy in my life.

Craig Chepke, MD, DFAPA: I’ve seen the same thing. And I mentioned that we all have esketamine clinics. That set the bar pretty high for me in terms of a new mechanism of action, NMDA [N-methyl-D-aspartate] antagonist. And when the AXS-05 came out, I thought, “How can this be a medication that’s going to be transformative?” But I’ve seen what you have as well, Greg, [and] I’ve been really taken aback by how for the right patient, this has been really transformative for them. The accessibility of an oral agent, as you said, Erin, can’t be overstated because there’s so many people for whom an intervention like esketamine just isn’t an option for one reason or another.

Gus Alva, MD, DFAPA: Is there a drawback with the dosing regarding the oral option, though?

Craig Chepke, MD, DFAPA: It’s BID [twice a day] dosing, but I don’t think that’s particularly problematic. Most of my patients take something in the morning and something later in the day anyway, whether psychiatrically or for medical conditions, so honestly I don’t think it’s that big of a deal.

Greg Mattingly, MD: I’m going to give our audience one caution though, and you’ve brought this up before, Gus: Glutamate is good, but too much glutamate is too good. It’s not good, actually. It’ll overexcite nerve cells. So one of the cautions we have with that combination of bupropion [and] dextromethorphan is you start with 1 a day then you go to 2 a day and that’s the maximum dose. I would not go above that dose until we have safety data that [shows it’s] OK to go above it. And if you’re on a CYP2D6 inhibitor such as fluoxetine or duloxetine, you stick with 1 pill a day. And I just recently had a patient who tried to push the dose on their own when they were on a CYP2D6 inhibitor, and they didn’t do well. I think we need to know the safe and effective dose when it comes to these glutamate modulators.

Craig Chepke, MD, DFAPA: One thing that I like to say is NMDA is a really high-maintenance receptor. You’ve got to block it exactly right because there are work trials of memantine and of low motor gene and major depressive disorder. They didn’t work. You’ve got to have the exact right amount of NMDA antagonism to get efficacy and major depressive disorder. And the dosing-type scheme that was used for dextromethorphan-bupropion was scientifically engineered to have the exact number of milligrams of each agent to get the right blood concentrations of dextromethorphan to give you that right blockade of NMDA.

Erin Crown, MHS, PA-C: Which is why people should not try to make their own [combination], prescribing the 2 agents separately. To the CYP2D6 point that you made, Greg, it’s important for people to remember too that it’s not only psychotropic medications that can be CYP2D6 impacted. They can be on medications for other reasons that we need to maybe keep that at a single pill daily.

Greg Mattingly, MD: I’ll take it back to patients. I shared with you, Gus, that I’ve taken care of a young woman since she was a kid. She’s now in her 30s. She went on this combination of medicine…bupropion [and] dextromethorphan, and [came] back in December. It’s been pretty transformative. Not just in her personal life—and I know her husband, I know her kids. I’ve gotten to be an intimate part of their family over the last 20 years. But her business, her self-esteem, how she thinks of herself, all of those things [demonstrate how] the depression has been improved. It’s been remarkable to watch it.

Gus Alva, MD, DFAPA: I love that. When the rubber meets the road, that’s one thing. Sometimes we see clinical trial data that looks quite compelling and then subsequently we try it out in the real-world setting, and it’s lackluster. In this case, I would agree with you. I think that this has actually been a novel compound that is helping us greatly.

Erin Crown, MHS, PA-C: What I really want to emphasize about that are those long-term data. We briefly highlighted it earlier, but I think it’s really important to put it out there. So remembering [that] remission is our goal. We saw people in remission very early. We saw that remission sustained and across a year. We saw disability scores decrease and were sustained. We saw quality of life scores increased and sustained. Like this molecule is consistent and reliable.

Greg Mattingly, MD: If I remember the data, about 80% of people were in remission by the end of the year.

Erin Crown, MHS, PA-C: I think it’s 89%.

Greg Mattingly, MD: Yeah, 80-something percent. That’s about what we’ve seen in our clinical practice. I work with a group of psychiatrists [and] 6 nurse practitioners, and we’ve had about an 80% hit rate of getting people not better, but in remission. And that’s something we didn’t used to think about very often with an oral compound.

Craig Chepke, MD, DFAPA: You really couldn’t. We got used to what an oral medication for MDD [major depressive disorder] feels like, of what we expect, and we set the bar at a certain level, and I found similarly that using AXS-05 doesn’t feel like any other oral antidepressant I’ve ever prescribed.

Gus Alva, MD, DFAPA: The important benchmark that you address on right now is again results of the STAR-D study. But that’s again tying us back to that monoaminergic story and the subsequent benefit or lack thereof. We’re seeing things shift terrifically now.

Transcript was AI-generated and edited for clarity.

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