Experts highlight the role of NMDA and AMPA receptors in major depressive disorder (MDD) and how new therapies are targeting novel mechanisms of action.
Greg Mattingly, MD: You know, a dirty clinical secret, and we all know this: SSRIs [selective serotonin reuptake inhibitors] raise serotonin in the synapses by the very next day. But that mechanism takes weeks to months to really take effect. So it’s a downstream effect of raising serotonin that helps people when we do that. Same thing with norepinephrine and dopamine. We raise levels very quickly, but that doesn’t improve symptoms for weeks to months. This new mechanism, both GABA [γ-aminobutyric acid]-glutamate, when you hit that junction, you improve symptoms within hours to several days instead of weeks to months.
Gus Alva, MD, DFAPA: I’m really happy that you touched on that point, because our next question that I’d like to delve into is specifically that. When we think of depression, major depressive disorder, explain the importance of NMDA [N-methyl-D-aspartate] receptors or AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid] receptors, inotropic receptors, which includes kinase [receptors]. What mechanisms make them important therapeutic targets for major depressive disorder? I think that you, [Greg], were tying into this by looking at the rapidity of onset, but specifically the issues that are at play. It’s predominantly an intracellular process, but you’re seeing effects very quickly.
Craig Chepke, MD, DFAPA: With ion channels, as soon as you open that ion channel, ions are flowing, unlike the metabotropic receptors, [where] you’ve got second messengers, third messengers, fourth messengers, so on and so forth. Theoretically, that could be one of the reasons why you see such a long time to have the clinical effect, because it takes a while for those changes to be affected. That’s just one of the reasons. There are many reasons potentially, but I think that’s one key part. I’m glad that GABA has come up here because you really can’t talk about glutamate without talking about GABA. I think of it like the Fred [Astaire] and Ginger [Rogers] of the brain. Wherever one goes, so goes the other, and they do a beautiful dance together, always in harmony and synchrony to make sure that everything’s in the perfect synchrony.
Gus Alva, MD, DFAPA: I’m glad you touched on that, because there does need to be a balance, right? If that balance is off-kilter, obviously there are problems that are going to ensue.
Craig Chepke, MD, DFAPA: Glutamate is extraordinarily neurotoxic, so it has to be able to be balanced and recycled with the glia, and make sure that we’re not over-releasing it from the glutamate neurons with the GABA balance.
Greg Mattingly, MD: Let me give everybody out there just a basic kind of pharmacology, but it’s pharmacology that’s going to make clinical differences as you think about these compounds. AMPA and NMDA are ion channels that [allows] calcium [to] go inside the nerve cell. Calcium is positively charged, so it makes nerve cells want to fire. It turns them on, it activates them, it turns on neuroplasticity. GABA does just the opposite. It’s an ion channel, but it lets chloride go inside the nerve cell. Chloride is negatively charged, it makes nerve cell networks want to slow down. So just like Craig’s analogy, the 2 have to dance together, absolutely. They have to move in concert with each other. We don’t want that engine to go too fast, but we don’t get stuck going too slow either. It’s got to turn on and off together with each other.
Gus Alva, MD, DFAPA: That’s the difference between the ionotropic and the metabotropic type of an effect, right? Because if we’re waiting for that potassium to flux out instead of the calcium seeping in, you’re getting the exact same effect, but at a longer time frame. Absolutely true.
Transcript was AI-generated and edited for clarity.