Ketamine for the Treatment of MDD


Ryan Oakley, MD, takes a closer look at the recent history of ketamine in depression. He also explores the differences between ketamine and esketamine.


Ryan Oakley, MD: I'm going to be talking about the interventional options that move a little bit away from direct electrical stimulation, using a more advanced neurochemical intervention. I would be surprised if most of you haven't at least heard of ketamine at this point as being used for mental illness in some way. It's all over the news, it's being marketed for a lot of different things. We're going to discuss a little bit about what it has actual evidence for and clear some of that up, including talking about what the FDA just released to combat some of that marketing. We're also going to talk about the evolution and the creation of the FDA-approved insurance-covered form of ketamine, which is esketamine, and how we use that in our clinics as an intervention.

So, what's special about ketamine, why is this being developed as an interventional treatment? First, to understand where ketamine is right now what it's been used for, its primary use is the procedural anesthetic and medicine. It started being explored for depression specifically based on some animal studies that showed that, when intervening on the glutamate system, the animals depressed behaviors improved, also based on some human clinical studies with medications that act on the glutamate system, like lamotrigine or alprazolam, also found to have some antidepressant activity. So then, a group decided to see if we could intervene directly on the glutamate system with an NMDA antagonist, like ketamine, to see what kind of effect would that have on depression. This group did a study, a randomized controlled trial, double-blind crossover study, and showed that it did, in fact, have a pretty dramatic, rapid, and sustained antidepressant activity. It was then explored a lot more as a treatment for depression.

We talked about ketamine a little bit. Esketamine was developed later. Essentially, ketamine is a combination of two different mirror images of a molecule. Esketamine is one of those mirror images of the molecule that they've designed and created to be delivered intranasally in an office setting, which sort of improves its scalability (ie, how easily we can deliver this treatment). So that's where esketamine is. “Es” is actually the name of the mirror image of ketamine, [and] this how it gets its name.

So, breaking down the difference between ketamine and esketamine, the biggest one is which one's actually insurance-based, which one has approval. Ketamine is not approved by the FDA for any kind of mental health treatment at this point. It's also not covered by insurance. Esketamine is approved by the FDA for treatment-resistant depression or major depression with suicidal ideation. The FDA recently put out a warning on compounded ketamine, because ketamine is getting marketed almost like a snake oil treatment for all the different types of mental illness where there's not a lot of evidence to support it (except for in depression, IV formulation, and a specific way of delivery). Whereas esketamine has evidence, we have a well-defined means of how to deliver it.

[What are] other differences between them? Ketamine, the drug itself or the medication is actually quite inexpensive. Esketamine, the drug, is actually quite expensive. However, insurance covering esketamine actually makes it more affordable for patients, whereas ketamine treatments, you're not just paying for the medication, you're paying for staff, you're paying for monitoring, paying for IV, all these things. It actually becomes less affordable for the patient, whereas esketamine is a very affordable option for people with treatment and depression. Other things to note is that there's no federally mandated program that tells us how to use ketamine. There are no guidelines for it. Esketamine does have guidelines. Ketamine doesn't have a risk evaluation mitigation system. So, we don't have a place where we can find out more about the side effects of how safe ketamine actually is, whereas esketamine does have that. We're continually monitoring how safe it is, and also able to update information for patients to make sure we deliver it the most safe way possible.

Transcript was AI-generated and edited for clarity.

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