New Agents in Treatment of MDD

Andrew J. Cutler, MD: Sagar, there’s a number of glutamatergic GABAergic, and now, of course, we’ve got to talk about psychedelic drugs in development. Can you talk a little bit about some of these medications, which patients they’re approved for, and the data? I’m going to mention a couple of these. We’ve talked about intranasal esketamine. Can you tell me a little bit about that one and for whom it’s approved for?

Sagar V. Parikh, MD, FRCPC: Yeah. Just before I do that though, I’m going to make a chicken or egg analogy here around our old monoamine neurotransmitters. There’s no doubt that all of these new agents work immediately on other systems like GABA glutamate, but all of these systems are intertwined. And it may be that by enhancing synaptogenesis and perhaps by recruiting other additional mechanisms, what they really do is enhance the function of the monoamines. I don’t think we should think of this like, “Wow, we never knew that there were these chemicals that have a totally different action on the brain.” I sense they probably have some mechanisms, which are truly parallel systems that invoke other things. But I suspect that GABA and glutamate end up modulating our traditional monoamine much more efficiently and much more than we think.

Andrew J. Cutler, MD: Well, that or the other way around. But the point is we shouldn’t throw the baby out with the bath water, of course, with the monoamines.

Sagar V. Parikh, MD, FRCPC: Right. When we think about several of the newer agents, they’ve said, “OK, why not think about GABA and glutamate?” When we think of novel mechanisms, No. 1, can we affect GABA receptors? And then what happens? And No. 2, can we interfere with glutamate receptors? And glutamate really has 2 main receptors. It has AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid] receptors and NMDA [N-methyl-D-aspartate] receptors. In a sense, we have 3 different types of receptors that we can use to modulate the GABA glutamate system, So, I think the newer medicines pick and choose which direction they’re going to go. Are they mostly going to affect GABA receptors or are they going to affect AMPA and NMDA receptors?

Andrew J. Cutler, MD: Well, actually, Sagar, there are hundreds of glutamate receptors and they divide into metabotropic and ion channels. There are drugs in development for all of these different receptors, believe it or not. And then GABA of course, we focus pretty much on the GABA-A system. There are GABA-B receptors that are metabotropic, but GABA-A is an ion channel as well.

Sagar V. Parikh, MD, FRCPC: That’s right. There are many more targets. So, thinking about it broadly, we can simplify it with -more GABA-focused or more glutamate-focused interventions. Coming back to esketamine, that’s been approved since 2019. It was the first drug that really was approved in this category that presumably works primarily on the NMDA receptor and some related mechanisms. What was interesting is, unlike a lot of our other treatments, it was always meant to be, at least in its approval co-administered with a traditional antidepressant. I suppose that was a more cautious way of looking into how it might be used, particularly since it was used for treatment-resistant individuals who might be getting a little bit of benefit from traditional antidepressants. So, you didn’t want to strip them naked and then put them on a new monotherapy. That has, I think, a pretty good track record now. It’s been out for several years. I think we’ve all had a reasonable amount of practical experience. IV [intravenous] ketamine, of course, does not have an FDA indication, but also has a reasonable amount of evidence and surely shares most of the same mechanisms as esketamine. That would be one category of medication. The other focus on GABA, particularly with zuranolone would offer the stimulation of the GABA-A receptors. And that’s, again, a different mechanism. Then the third thing that we’re hearing a lot about is psychedelics. And the serotonin 1A receptor may be particularly pertinent there.

Andrew J. Cutler, MD: Well, it’s 5-HT2A [5-hydroxytryptamine receptor 2A]. Sorry to interrupt. They’re 5-HT2A agonists, actually.

Sagar V. Parikh, MD, FRCPC: Right. And so, they do represent different strategies. And what’s interesting is that they, for the most part, offer much more rapid relief than our traditional approaches.

Andrew J. Cutler, MD: Yes, it’s interesting. Back to your original point, the psychedelics are working through the serotonin system, our old friend, serotonin, but it turns out that 5-HT2A receptors are heavily located on pyramidal glutamate neurons in the cortex and that you may be affecting glutamate, as you mentioned earlier, transmission, from the top down. Greg, before we get zuranolone, there is a medicine on the market called brexanolone. Tell me about that.

Gregory Mattingly, MD: Brexanolone, it’s a derivative of a natural neurosteroid that we all make called allopregnanolone. Andy, I know you and I have been involved with some of the trials on this whole family of molecules. There’ve been in development now for the last 10, 15, 20 years. We all make these chemicals in the brain that we call neural steroids. They bind to the GABA-A receptors and they tend to be that crosstalk between GABA and glutamate, which I think of as the gas pedal and the brake in the brain for these neural networks. Those things have to work in concert. The theory was, what if these neural steroids somehow aren’t functioning the way they should, maybe because a woman is going through a postpartum period? She’s had a drop in these during her pregnancy. Maybe that receptor has gotten stuck, so it’s not firing the way it should anymore. Some studies were done- asking, “Could an IV version of allopregnanolone called brexanolone be given to women?”

Could we give an IV infusion of a very similar molecule and reset the thermostat in women that have postpartum depression? If you look at that data, Andy, I think it was what, a 60-hour infusion? What we found is somewhere between 70% to 80% of women with postpartum depression had their depression in remission after the 60-hour infusion. They were pretty much back to asymptomatic conditions. Many of them never had a recurrence of depression after they had a single IV infusion. That’s then led to, OK, can we find a molecule like that that can be given in an oral version that crosses the blood-brain barrier that has good permeability? So, some exciting times looking at this group of medicines we call the neural steroids.

Andrew J. Cutler, MD: Yeah, I agree. Interestingly, intranasal esketamine is approved for treatment-resistant depression. Brexanolone is for postpartum depression. The newest on the market is AXS-05, which has a brand name now, but it’s the dextromethorphan-bupropion combination. That’s approved for depression, not TRD [treatment-resistant depression.] It’s interesting, I hadn’t known a whole lot about the pharmacology of dextromethorphan until a few years ago, but dextromethorphan is a serotonin reuptake inhibitor. It’s an NMDA antagonist, and it’s a Σ1-receptor agonist, which is an antidepressant mechanism and an anti-inflammatory mechanism. The data is quite interesting with this drug. They have data that it works better than the bupropion component alone. And it had data that it actually works within the first weeks. So, to our earlier points where a lot of medicines take several weeks to work, they’re actually able to claim relatively early onset within the first week. But as we’ve talked about, some of these other medicines work even sooner than that. Greg, you said within a couple of days or even within a few hours; in some cases, within 24 hours.

Transcript edited for clarity