Transcript: Ketamine, a Quick Guide to Receptors

October 1, 2014

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DR. RAISON: Hi, I’m Dr. Charles Raison. I’m with the Steering Committee for the U.S. Psychiatric Congress. I’m here with Dr. David Nichols. You’ve got so much expertise on how receptors work, and of course so much of our field is based on modulating receptors. 

For years we’ve mostly focused on dopamine, norepinephrine, serotonin, but clearly in the last couple of years there’s been an explosion of interest in the NMDA receptor. Can you talk to us a little about what we know about why something like ketamine seems to have this rather powerful and rapid antidepressant effect? 

DR. NICHOLS: Well, you’ve asked the unanswerable question. I think in 2000 the first study was done, with seven subjects, showing that it had a dramatic antidepressant effect. The problem with treating depression is that there’s been this paradigm that you have to increase synaptic levels of monoamines, so every antidepressant that they’ve developed has been one that’s increased serotonin, increased norepinephrine, or both. 

And so now, within the last five to ten years, there’s really been an explosion of interest in the fact that ketamine, which is an antagonist of the NMDA type of glutamate receptor, has a robust antidepressant effect that manifests literally within minutes. And no one really understands how that works. We know that it blocks NMDA type glutamate receptors. Those seem to be on an inhibitory type of GABA interneuron. So the GABA interneurons, if they’re active, they’re releasing GABA, which is inhibitory. So they shut down other glutamate systems, so when you block the glutamate activation, you shut off the GABA tone, and then those glutamate neurons start spilling out glutamate. 

DR. RAISON: So it’s paradoxical. Really, you say, ‘it’s an NMDA antagonist’ so we’re blocking glutamate signaling, but because of its location, you’re actually potentiating—

DR. NICHOLS: What you actually see is an increase in glutamate. If you did a microdialysis experiment and you put in ketamine, what you see is an increase in glutamate. So you block NMDA type glutamate receptors, but you increase— 

DR. RAISON: In the synaptic space. 

DR. NICHOLS: Right, in the general area. And so that glutamate presumably activates GABA and AMPA receptors. 

DR. RAISON: Which are different glutamate receptors. 

DR. NICHOLS: Right. They’re in that same family. They’re ionotropic. Now, the cascade that follows that is what everyone is focusing on now—what’s actually happening there. We know now there’s probably an increase in BDNF, which is decreased in depression, so that may be one thing that’s happening. And that would increase synaptogenesis in the hippocampus. 

Right now though, they’re just trying to put together the pieces. The other thing that’s really puzzling is why [the effects of ketamine] only last for 72 hours or so for most people. 


DR. NICHOLS: You get this immediate effect, and then it wears off. What’s happening? And if they can solve that problem, that will really be a breakthrough.

The other issue is that ketamine is psychoactive and produces these psychotomimetic effects. And so they’d like to find some kind of NMDA antagonist that doesn’t do that. I’ve seen a couple of studies where they’ve used memantine. I don’t know how well that works. 

DR. RAISON: I don’t think it does. The interesting thing is that other NMDA antagonists are not the same kettle of fish. They don’t seem to have that same potency. 

DR. NICHOLS: And there’s another interesting thing with this rapid onset. In patients who are acutely suicidal and come in—what do you do? Well, boom, you might be able to give them a day or two of alleviation of that. 

And then there’s at least one study where they use ketamine as anesthesia for ECT. That produced better response, and usually it takes five or six sessions of ECT. This was one session, so there’s a lot of interest in that too for refractory patients. 

DR. RAISON: Thank you. Fascinating, cutting-edge stuff.