Responding With Treatment: Clinical Perspectives on First MDD Case


Experts continue their discussion of the first patient case, explaining how glutamate-modulating therapies could help improve his symptoms and outcomes.


Gus Alva, MD, DFAPA: To be even more provocative, let me give you a little bit more information. His primary care doctor started him out on a serotonin-specific reuptake inhibitor. And within the first few weeks, he started to get some benefit associated with the medicine, he was being monitored. This continued for approximately 6 months. There was a partial response that was noted there, but he continued to have residual symptomatology, including persistent feelings of sadness, sleep disturbance, and irritability. So is that something that you sometimes run into, Erin? In a specialty clinic, you wouldn’t necessarily see this individual right away, but you might subsequently see them because they’ve got additional things that are tethering them toward disability.

Erin Crown, MHS, PA-C: Certainly, I’ve seen this individual and many like this individual. It’s important for us to remember that there’s really no evidence to support giving them another SSRI [selective serotonin reuptake inhibitor], right? We could expect probably more of the same if we do that, right?

Gus Alva, MD, DFAPA: So are you saying then that we should incorporate Greg’s provocative point of maybe looking at things from a different angle than what we’ve been looking at?

Erin Crown, MHS, PA-C: I’m happy to endorse that viewpoint, yes.

Greg Mattingly, MD: I found myself getting frustrated and even a little bit irritated and angry when I listened to this case. My heart kind of broke for him. If we had a cough, we wouldn’t sit at home for 6 months coughing. If we had a fever, we wouldn’t sit at home for 6 months with a fever. If we had a migraine headache, we wouldn’t sit at home for 6 months with a migraine. But yet this gentleman has been struggling with depression. It’s only partially better for 6 months. And it happens in all of our practices. We’re all guilty of it. So I think changing even that thought model, you don’t have to just sit and struggle for 6 months. If you’re not better after a couple of weeks, we should be doing something different. We have new treatment paradigms that look at urgent response, not just long-term kind of struggling.

Gus Alva, MD, DFAPA: Based on that, how would you approach it, Craig?

Craig Chepke, MD, DFAPA: Well, one thing just to point out quickly, the residual symptoms included sleep difficulties and irritability. So always when someone’s having a less than optimal response from any depressant, [we] make sure we’ve got the right diagnosis, that we’re double-checking again, triple-checking. Do they have bipolar depression? But rolling that out, then, as Erin said to me, that man’s brain has proved to me that he is not a responder to monoamine reuptake inhibitors. And I’m going to go with a different mechanism of action. It’s a specific targeted therapy that is hitting a specific receptor, which could mean atypical anesthetics, or something that is completely out of the monoamine realm, like one of the glutamatergic agents. We didn’t hear of suicidality…and he’s only had 1 antidepressant treatment. So as ketamine isn’t really indicated at this point, but dextromethorphan-bupropion would be indicated for this individual and I think would be kind of a perfect fit, as Erin mentioned, with the specific symptom cluster of the low motivation and potentially anhedonia and the cognitive difficulties, that would be something I think would fit really well with that. The rapid response after having sat there for 6 months of feeling just like a shell of himself would be something I’d really want to offer him, because in that tough job he could be on the chopping block. He could be fired any day, and that’s going to be way on his mind and causing him a lot of stress and continue to maintain that those feelings of depression.

Gus Alva, MD, DFAPA: I love the way that you threaded the potential for either again a change or a switch versus augmentation, and you know I really like the fact that you stress that point, and then you obviously steered it toward this individual’s clinical history. Sometimes a bit of persistence is met by individuals who say, “Wait a minute, why are you giving me this type of medicine if it’s also utilized to treat other things?” Whereas you know there may be a treatment modality that might address the particular condition that we’ve tried to elucidate the additional insight for forum to help them comprehend what it is that we’re trying to accomplish.

Greg Mattingly, MD: Greg, as I was thinking about him, 4 things went through my mind. No. 1 is we could switch to another antidepressant, [which] probably would be done commonly. The negative there is you’re going to be waiting another 4 or 8 weeks, and the answer is it’s honestly diminishing returns, it’s another 4 to 8 weeks. We could augment with bupropion, done very commonly, not FDA approved, but done [commonly]. I’m going to give a take-home to the audience: I’ve been a part of 3 trials where we did bupropion augmentation [and] it didn’t work as well as we thought it would. That’s why there is not a combination pill—it’s been tried and tested by many companies; it works a little bit [but] not enough to get an FDA indication. That’s why that combination has never been FDA approved. The next combination would be an atypical in a psychotic that is FDA approved or going straight to the oral medicine, [AXS-05], with bupropion plus the dextromethorphan with glutamate. I think then you’re weighing the pros and cons of an atypical in the [adverse] effects versus going to a glutamate approach in the [adverse] effects there.

Gus Alva, MD, DFAPA: I’m glad you emphasize that point, Greg, because obviously the bupropion component with dextromethorphan is to inhibit the 2D6 hydrogen enzyme pathway, not to lead the charge regarding the overall clinical benefit. Clinical benefit is dominantly coming from dextromethorphan.

Craig Chepke, MD, DFAPA: AXS-05 is a dextromethorphan story, not a bupropion story.

Erin Crown, MHS, PA-C: And it was studied head-to-head against the very amount of bupropion in the combination treatment as well, and it still separated and still was very consistent.

Greg Mattingly, MD: Triple the response.

Gus Alva, MD, DFAPA: Precisely.

Transcript was AI-generated and edited for clarity.

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