The Role of Esketamine in the Treatment of Treatment Resistant Depression


Hanita Chhabra, MD, highlights safety and efficacy data of esketamine and shares practical implications for clinical practice.


Hanita Chhabra, MD: Our next slide goes into the actual efficacy of esketamine, the phase 3 trials that have been produced that resulted in the FDA approval. The TRANSFORM studies I, II, and III were the initial FDA approval, completed and published in 2019. These were randomized, active, controlled, [and] double blind. Neither the provider nor the participant was aware of what was happening. They were using intranasal esketamine with an antidepressant or they were just getting a placebo intranasal spray with an antidepressant. In order to meet criteria for the TRANSFORM studies they did have to meet treatment resistant depression (TRD) criteria; so [they] failed at least two antidepressants in this episode of depression and have a severe depression. This study showed a significant or statistically significant improvement in the MADRS scores for the antidepressant with nasal ketamine as opposed to the antidepressant with placebo nasal spray. The SUSTAIN trials one and two were looking at the long-term benefits or remission of depression with esketamine treatment compared to the antidepressant, with the placebo alone, as well as the safety. And finally, the newest FDA indication that major depression with suicidal ideation, that is the results of the ASPIRE study showing that very robust and rapid antidepressant effect that you get within 24 hours or less of nasal esketamine.

We touched on [side effects] a little bit with how the REMS program was created. And I did take this from Spravato Health Care Provider website strictly because I liked how they ranked it in order of what's most common and what's least common. Most likely folks will dissociate. But I want to clarify, this is not dissociation in the way that providers or patients dread. It's not an alter appearing that you were not familiar with and catches you completely off guard. It's a very mild body mind disconnect. So, what I most commonly here is the clients reaching for their glass of water. They're drinking water, but it doesn't feel like it's their arm bringing the cup to their mouth. So, it's a subtle mind body disconnect. Dizziness can be quite common, as well as nausea and sedation. That's the most of what we see. And mostly we see that in the first 20, 30, at the most 40 minutes of treatment. We're often initiating nasal esketamine in the lower dose, which is considered 56 milligrams, which looks like two of those inhalers I showed you. It's inhaler one, wait 5 minutes, dose the second inhaler. That basic dose is 56 milligrams. I often stay there the very first treatment exactly for this reason I want to monitor what's going on. How much, how much of any kind of sedation is there? How much dizziness is there? Can they safely walk to the bathroom? Is there a lot of nausea? If there is, before they get to vomiting, I'd rather put in something like Zofran for them. It's very rare that I need an antiemetic medication, but that's one of the things I'd rather elucidate and clarify prior to going to the higher dose. For me, the main two reasons of staying at the lower dose and really monitoring in-office as opposed to absolutely home usage of these kinds of medications is the risk of anxiety and the risk of blood pressure. I'll just touch on those slightly. Anxiety is a big one because as most of us know, anxiety and depression are often co-morbid, and I don't want you to worry that you're giving a treatment to your clients or recommending a treatment that could worsen their anxiety. Most often, the majority of the time, nasal esketamine is an incredibly positive experience. The body's deeply relaxed. The mind is very alert. It's often [like] virtual reality; people tell me it feels like a video game. They're seeing flashes of the past, flashes of future. It's a lot of light. It's very colorful. It gets them thinking about the future again in a way that's much more upbeat. But sometimes it can be an anxious response. It can be that I'm being chased by these demons, I'm falling into a hole, and I can't get out. I can't breathe. That's why we're here. That's why we're monitoring patients closely. We can remind them that they're safe. They've been given nasal esketamine. It's going to wear off within the next 20 to 30 minutes, no matter what; no matter how anxious their response, they're still going to have a profound depression relief over the next few days. Really just talk them through that. And [it's] same thing [with] blood pressure. A lot of clients will have a transient increase in their blood pressure, but we need to make sure that it's not so high they can have medical complications, or so high on an ongoing basis that it would lead to like a chronic overuse of the cardiovascular system. So those are the majority of the adverse events of the effects that we're looking out for.

I'll end with contraindications before Dr. Grammer takes us home and really ends with a bang and focuses in on the adverse effects and contraindications in more detail. But obviously, one contraindication is uncontrolled hypertension. If your blood pressure is not well regulated, you're not compliant with your medications, we need to make sure that happens before we administer any less ketamine.We don't want your pressure to go so high that you're getting into hypertensive urgency. If you have a history of any kind of arterial vascular malformation, vascular abnormality, aneurysm, anything that could predispose a vessel to burst that is a contraindication to nasal esketamine. If there's been a history of intracranial bleeds, even if it was trauma induced, that's a relative contraindication esketamine. So [we] really need to take a very careful look at risks versus benefits in those situations. [In addition], pregnancy and breastfeeding, simply because we don't have the data; we don't have enough data to support the safety of usage in either of those scenarios. And finally, a known allergy or hypersensitivity to ketamine or ketamine.

Transcript was AI-generated and edited for clarity.

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