Cognitive Wellness: The Potential of Glutamate Modulation for MDD


Clinicians discuss the effects of glutamate modulation on neuroplasticity, memory, and cognitive function, highlighting their role in improving overall wellness for their patients.


Gus Alva, MD, DFAPA: Erin, we were touching on issues associated with experience and learning, memory, motion, and the processing of emotion. Obviously, Greg was tying in that dendritic growth and the spines being all of a sudden allowed to be pruned appropriately and regenerate. That’s ultimately what we want seeing in a healthy brain. So this sounds like a good input along the lines of being able to accomplish all of those things.

Erin Crown, MHS, PA-C: I think that it is, when I talk to my patients about some of these treatment options, or when I speak with my colleagues and help them better understand mechanism of action and why it matters. Mechanism of action matters in psychopharmacology, and it matters in the treatment and symptomatology of our patients. When I talk to people about it, I kind of describe it like this. All that stress and inflammation results in the dendrites of our nerve cells to kind of become these shriveled-up trees, like winterized trees. We’re coming on winter here, the leaves are falling. They become these kind of winterized trees. When we modulate glutamate in these ways and we reduce that inflammatory response and we allow for neuroplasticity and neurogenesis to occur, it’s more like the trees in springtime or the trees in the summertime, those dendrites really kind of come back to life. We can see that occurring, and it’s very exciting. So when we think about cognition especially and how impaired cognition can be in individuals suffering from major depressive disorder [MDD], that’s a meaningful piece of information to have. They can also instill some confidence in our patients related to symptoms that they’re experiencing as well.

Greg Mattingly, MD: Gus, I know you and I do research in a lot of different areas of mental health, and you learn from one area about another area, right? So one of the things when you talk about cognition, one of the key areas of the brain that gets involved with cognition is the hippocampus. And we know the hippocampus gets damaged by depression. The key neurotransmitter there that turns on the process of laying down a new memory, it’s not serotonin, it’s not norepinephrine, it’s not dopamine, it’s glutamate. Glutamate has to turn on that firing in the hippocampus, that’s 3A3 level, for us to lay down a new memory. So when we talk about why have certain antidepressants, our monoamine antidepressants, they’ve been great for certain things. But they haven’t been great for cognition. They haven’t been great for reward. They haven’t been great for motivation. They haven’t been great for anhedonia. Those have been places where standard antidepressants haven’t worked. So when we look at these novel targets, we say, what are those residual symptoms that we still have a chance to target with some of these new molecules?

Craig Chepke, MD, DFAPA: Yes, the standard antidepressants can help people to stop lying in the fetal position, crying in bed. They can get out of bed, but can they go to work? Can they play with their kids? Can they do their taxes? Can they do the things that they want to do to achieve wellness?

Gus Alva, MD, DFAPA: Feeling energized? But calm at the same time. Yeah. Feeling that sense of self-esteem and the ability to reach happiness.

Transcript was AI-generated and edited for clarity.

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