Narrator - Dr. Abel  00:00
Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast

Narrator - ?  00:11
is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy.

Narrator - Dr. Abel  00:17
This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider.

Narrator - ?  00:27
And now on to the show.

Dr. Sean Kane  00:31
Welcome to HelixTalk. Episode 96 I'm your co host,

Speaker 1  00:33
Dr. Kane, I'm Dr. Schuman, and I'm Dr. Patel, and this week I'm excited to bring to you HelixTalk. Episode 96 Abracadabra spravato is esketamine A new magic cure for depression.

Dr. Sean Kane  00:44
It sounds like today we're talking about a new drug that sounds like a ketamine derivative to me. Dr. Schuman, yeah.

Speaker 1  00:50
So what we're going to talk about is the recent FDA approval of esketamine, brand name, spravato for management of treatment resistant depression as an add on to oral antidepressant therapy. So it's a novel agent in its mechanism of action and in its dosage form, and even a little bit too in terms of its adverse event profile and the logistics of administration. So there's a lot to cover. The history of it, what it looks like, and maybe, you know, is this a really as big of a deal as it seems to be?

Speaker 2  01:16
So I'm really intrigued to learn what esketamine is. However, let's, let's talk about what ketamine is, because it sounds a lot like that. So we know it was a, it's an NMDA antagonist that was approved as an anesthetic agent back in the days. But then we saw a lot of it used in veterinary medicine, and then, obviously, some drug of abuse, type of uses, as well known as Special K or cat Valium, and mainly the use there was for its hallucinogenic effects, right?

Speaker 1  01:46
So they know things like loss of awareness, of time and space, depersonalization, derealization, vivid dreams, flashbacks, as adverse effects people talk about is falling into the K hole. So it doesn't sound like one of those things that could be a good thing, but it does have a lot of uses. Dr. Kane, I'm imagining you see this every now and then as an anesthetic agent,

Dr. Sean Kane  02:05
for sure. So we use ketamine fairly commonly. It's becoming more common in the hospital setting for a variety of reasons, one of which is that it doesn't cause respiratory depression, unlike a propofol, for example, and it has a number of properties to it that are just kinetically good. So it doesn't have a long duration of action for its anesthetic effects. It's definitely making kind of a comeback in the ICU world, which is interesting that you brought it up as this more outpatient medication, yeah.

Speaker 1  02:32
So starting the last few years, when I about two or three years into my career in Psych pharmacy, started hearing more about ketamine, and right in 2013 was given this breakthrough designation from the FDA based upon this data showing a rapid onset of relief of depressive symptoms, and that's something I'll get to later. What that means, but it's it does some things unique, doesn't it? That doesn't look like the the typical thing that we think about how antidepressants work. And so now, as of March 2019 it's got this FDA approval as an adjunct to oral antidepressants for treatment resistant depression.

Speaker 2  03:04
So you said treatment resistant depression sounds like, almost like a particular set of major depressive disorder. Can you talk a little bit about what the definition of treatment resistant depression is?

Speaker 1  03:16
And this is really important, because it looks at, you know, to evaluate what did the data actually show as well as, how can we apply this our patients and our patients candidates? And so the company in the FDA, it's actually one of those that you could go down the rabbit hole of reading the documents, and they really went back and forth about, how do you define this? So the company and the FDA had to agree on it. What they said was, need, you need two failures of agents, antidepressant agents, orally, an adequate dose and duration for six weeks during the current episode of depression. Some people say, Well, you know, two failures regardless. Maybe you failed it once in an episode three years ago, you failed another agent. Now they said, No, you have to have, in this current episode of depression, failed two different agents. And also they gave definitions as far as what's an adequate dose. And so for the interest of time, won't go through that, but there are tables saying you must reach this dose for six weeks, and it's important, though. For example, a patient who's on escitalopram (Lexapro) 5 mg/day, or mirtazapine 7.5 mg/day, even if it was for six weeks, that would not meet definition. So you would have to advise the provider and the patient, keep escalating the dose up higher, see if they tolerate it, and then we'll go from there.

Speaker 2  04:21
This definition is probably created to make sure that you're utilizing the first line treatment appropriately at appropriate duration of time before advancing to a medication like esketamine, right?

Speaker 1  04:33
And it's important, though, because, like with schizophrenia, it's been really hard to define treatment resistant schizophrenia, so the fact that they came to a pretty good agreement consensus here. For treatment, this impression is a good thing, and

Dr. Sean Kane  04:44
that makes sense. Like to call it resistant, you have to give an adequate dose and an adequate duration of time, a minimum of six weeks, to make sure that they are truly resistant and that you haven't, kind of not given them an adequate trial yet. And there are

Speaker 1  04:57
some other things that are on the market right now for treatment. Resistant depression. Symbyax is the one medication which does have FDA approval, not only used a whole lot, it's a combination of olanzapine and fluoxetine that are at different dosage strengths than what you could make if you were to just do it together with some duct tape. I mean, you can, you know, you can still prescribe somebody a little bit of olanzapine, a little bit of fluoxetine. The dose is different on that product. But other things you can do are ECT, electroconvulsive therapy, transcranial magnetic stimulation, vagus nerve stimulation, there's some things like that. So we do have other options. Now.

Dr. Sean Kane  05:28
Is this different than an adjunct for major depressive disorder versus treatment resistant depression?

Speaker 1  05:33
Yeah, so that's an important thing to note. Is there are medications. A number of the newer atypical antipsychotics, aripiprazole, brexpiprazole, and quetiapine. All have those indications as adjunct but not specifically for treatment depression. So what that should mean, then is, when you look at the study data, these are going to be patients that have generally non responders on a whole lot of other trials, kind of the more difficult to treat.

Dr. Sean Kane  05:55
And maybe that's a good thing, that we're now studying a population that is harder to treat, that is refractory to our conventional therapies, as opposed to, kind of another first line agent for depression that is as good as everything that we already have. Now, we're kind of targeting a patient population that's harder to treat,

Speaker 2  06:11
yep, and then perhaps this kind of fits the unmet need as well for those patients. So the big question, and I like to quiz students on rotation, is, how does that really work?

Speaker 1  06:21
And that's a tricky thing. So when I was again, first starting out that they didn't really know, and they've kind of come up with a theory. It's possible that it's an imbalance of glutamate, and thus NMDA antagonism is necessary. But some believe, and this is, I think, more the theory is that by blocking the NMDA receptor, it increases signaling of AMPA, which is another ionotropic glutamate receptor (AMPA). And so by increasing that one, you end up with some neuroplasticity. You end up with with changes in amount of in connected connectedness of the cells, as well as more of an increase in brain-derived neurotrophic factor. So the connections within the brain get a little bit better from an excitatory system

Dr. Sean Kane  07:03
and s ketamine. You know, I'm familiar with just ketamine. I'm assuming the S is an enantiomer of ketamine.

Speaker 1  07:08
Yeah, so the S enantiomer has a greater effect in blocking NMDA and also has a greater affinity for the dopamine transporter, so it's overall more potent than the R ketamine form. Unfortunately, though, it is metabolized more rapidly in the S‑ketamine form than the racemic form of the combination, so the half life in the plasma is only two to three hours.

Dr. Sean Kane  07:28
So then I'm assuming, based on the FDA approval of treatment resistant depression, they probably studied patients who met that

Speaker 1  07:34
criteria, right? Yeah. And so it's interesting that initially they were going to try to do it, and then some of the initial paperwork that came out from the FDA. They said, We're going to go ahead and study this in patients who failed an antidepressant, and then they were going to receive esketamine on top of that antidepressant, just to see if that helped any. And the FDA kind of said adding a medication to a failed treatment in TRD was, 'not sound clinical practice.' So there was an ethical issue there about saying, Hey, you're feeling really, really lousy on your medication, why don't you just go ahead and continue it, and we're going to randomize you to get placebo on top of that, or to get this new drug on top of it. So from an ethical consideration, they didn't really want to do that. So instead, what they did is they said to patients who had treatment resistant depression, and again, to give a number. So if they didn't get a 25% reduction in symptoms after using two agents during that current period of depression, they would receive one of four new to them, antidepressants, plus ketamine or placebo. Now the thing about that, though, is if they had already tried all four of those antidepressants, they would be excluded from the study. So there may have been some patients who were truly, really, really resistant, who had used all those medications. And so those medications, duloxetine, venlafaxine ER, escitalopram, or sertraline. So one note of it, yes, is for a patient that literally has failed, you know, 20 of them. If it included all four of those, they wouldn't be in the study. So may not represent that population.

Dr. Sean Kane  08:54
But I think that's also pretty reasonable. I can't imagine that that many patients will have failed those four therapies. So there's some balance here between totally resistant patients and someone who's never tried more than one. SSRI, yeah, really,

Speaker 1  09:07
I can only think of one or two patients off the top of my head that I have currently in our clinic that have that would meet that of failing all of those. But the other thing is that they use the MADRS (Montgomery–Åsberg Depression Rating Scale). It's a 10-item questionnaire. They score from zero to six, higher scores are worse. Again, response is 50% or more. And then it's divided into moderate depression, which be 20 to score a 20 to 34 anything above that would be considered severe. It's not really one we use in clinical practice a lot. I think some of our providers do. I usually use the PHQ nine. It's a little bit more straightforward, and that's the patient kind of self rate. And the other thing too is, you know, diagnosis has to be clear cut, so they excluded obsessive compulsive disorder, autism, psychotic disorders, things like that too. So we're thinking, this is a pure, clearly defined treatment resistant depression based upon, you know, very black and white parameters.

Dr. Sean Kane  09:57
I'm guessing that — is it the MADRS score? Yeah. I'm guessing that that is more of this, like research tool that is more complicated, but maybe gives you a better sense of some of these symptoms, because there's just more stuff in there to assess. Yeah, it's

Speaker 1  10:10
a gold standard for some of the for those from the clinic or from the research stuff side of things.

Speaker 2  10:14
So those clinicians who want to use esketamine in their clinical practice will have to utilize that tool to either start the patient or assess the efficacy. Is that correct? Probably.

Speaker 1  10:24
And again, it's not too much of a stretch to use that one as well, because most providers are fairly well aware of it. The other thing about this, in terms of the data, was, even though this one has shown some benefit in suicidality, that's what they weren't they were not looking for here, so anyone with suicidal thoughts in the past six months or actions in the last year, excluded. The other thing was, patients with coronary artery disease, QT interval greater than 450 or other major medical conditions were excluded. I believe a lot of that was concerned we'll get to later, but an increased blood pressure that was noted in some of the data,

Dr. Sean Kane  10:55
so I mentioned, at least in the ICU, one of the reasons we like ketamine is that it's a good option for patients who are hypotensive, it doesn't make the hypotension worse, whereas some of our other agents can cause that. So it's not surprising to me that tachycardia and hypertension, if the drug causes those things, that maybe you'd avoid this drug in patient populations that may be sensitive to that, in terms of coronary artery disease as an example, right?

Speaker 1  11:19
And so that's going to be something to go back to, because, again, that the data and Dr. Patel, when we talked about lectures on diabetes and depression, the diabetes, metabolic conditions, heart disease, are rampant in a population with mental illness. And so there's that that may serve to be a concern for it for a number of patients, as you look at applying the data. But first, let's see what the data even says. So the first one to kick it off was study 3001 better way of calling it transform one, patients with major depressive disorder who had failed one to five agents in the past and were on a new agent for two weeks, so they had to kind of start a new medication, or be in that process with their provider. Then if they still didn't respond to that agent, they were started on a new agent, which is one of those four ones within the study. So you kind of had to take some steps there again to show that you failed a couple of agents. And now you would be starting on this new agent. And then we wanted to know is that new agent you've never been on before, plus esketamine, and then using it at a couple different doses, so 56 milligrams, or 84 or placebo for four weeks. So it's a fairly complex design for the study, but I think they were did a good job of trying to balance the ethical piece of it, of making sure that the patients had a medication that they that could actually be working for them, and then to see if the esketamine did as well as to kind of explore the esketamine doses themselves. So then,

Dr. Sean Kane  12:39
just to clarify, in this study, everyone got one of the four new medications that you mentioned, and they gave two different doses of ketamine or placebo, and compared all three groups, right?

Speaker 1  12:50
And so this one actually, what was interesting is that they compared P value to point 025, and the higher dose actually did not separate from placebo. So that was a little surprising. In this first study. The good thing about it was they did a number of other studies, and some of them were mirrors of one another. So study 3002, or transform two set up very similarly. Again, in the structure, you had to fail number of agents, one to five in the past, and then you had to be on your newest medication, not respond to that one, then get randomized to a new agent, plus s ketamine or placebo, and this time, though, with a very similar study design, it did separate from placebo. And the most important thing with it, though, is the separation was seen as early as day two. So when I talk to you all, so you know, again, what do we you know, as far as when you say the patient, we're gonna start antidepressant. It's gonna take how long to start working? I'll tell them, six to eight weeks, yeah, and you may see something in two weeks, but really the robust response, if it happens, is four to six weeks to see something again. It may continue as you find the dose. To say that on day two, you separate it from placebo, and to say that, with the exception of one day, it was not significant. The rest of the four week period, every one of those, those endpoints is separated. That's a really alarming in a good way, thing that says this, this drug works, and can work very quickly.

Speaker 2  14:09
And so these two study the transform one and two, what type of delivery they use for esketamine, yeah.

Speaker 1  14:15
So this is, again, intranasal, and that's going to be one of the unique things about this medication that separates it, again, from, you know, where we use the ketamine clinics right now are more of an infusion clinic. That is something that's being done for depression, apart from an FDA approval. So this one has, and it's, it's, again, it's very unique in how they, they manufactured it.

Dr. Sean Kane  14:34
And there was nasal spray twice. So twice weekly,

Speaker 1  14:38
starting out as an induction, yes. And then from there, eventually you can go on further again. These were four there were four week studies. So they just kept it at that, twice weekly. So the other study was interesting is they still needed more data, you know, from from the FDA. And so what they wanted to do was, you know, another so we currently had one study that's positive. The FDA says you got to have two positives. Studies. Well, what they did is they used discontinuation study. Usually the FDA doesn't allow that, but that was something they allowed for this one so patients in the first two studies who remitted, so those patients whose MADRS score was less than 12 as the defined point, or they responded as a decrease in 50% they're then randomized at that point to getting the prior regimen of intranasal esketamine plus their oral antidepressant or placebo plus their oral antidepressant. So pretty much seeing if we take away your esketamine, do you get worse? And then they looked at the time to relapse or significant events such as hospitalization or suicide attempt. The only thing about that is that kind of comes up as an enriched study design. So you're you're pretty much only those patients. You're saying, I only need the patients who did well on it, and we're going to take away the drug you did well on and see if you don't. So it seems pretty intuitive that those patients are not going to do well when you take away the medication. So some feel that that's kind of stacking the deck at times in terms of data, but it is a good way of really seeing if the drug works by taking it away. And that's they noted in of those who remitted, quarter of the group relapsed in 33 days. And so they looked at the time to a quarter relapsing versus 153 in the esketamine group, so a much longer time. And then in responders: 25% of patients in the placebo group relapsed in 24 days (95% CI 17-46), compared to 217 days in the esketamine group. So we're talking about a large number of days of continuing symptom‑free if you were to stay on esketamine versus the placebo group.

Dr. Sean Kane  16:37
So it seems like if the drug works for you, and you have a response when you pull the drug away, you might go back and relapse into your depression then and again. As you said, it does kind of feel like stacking the deck a little bit, where you're only picking the people who were good responders and then seeing if they lack response. But it's still not nothing too Right?

Speaker 1  16:56
Yeah. And there was interesting that there was also another study transform three again, they were, they're really kind of running out of options for some of the names, I guess. But transform three was one looking specifically at patients older than 65 years of age who have failed anywhere one to eight agents in the past. And again, it was set up in the same design about being on a new medication they didn't respond. Put them on one of those four, plus esketamine or placebo. And this one, actually, I guess, just to get the spoiler on this one, they did not separate from placebo, so they were able to get the indication based upon one of their phase three studies of new patients plus the one discontinuation study. So as I said, Generally, the FDA doesn't consider those as counting for the two positive studies. But in this case, they said, We're going to make an exception, because of, you know, this is a pretty big deal. As far as you know, it's got this breakthrough approval and these other factors, which

Dr. Sean Kane  17:46
is actually kind of interesting to me, because this was not a long ketamine study, the first positive not the enrich study, but presumably patients are going to be taking this for a long period of time. In terms of, is that adequate data to allow for FDA approval. I personally don't feel like it is. I would want to see that second, larger, longer study to prove that that is an effective therapy for these patients. Yeah, and

Speaker 1  18:10
I believe a lot of that data should be coming out. It's gonna be interesting to see what it does. One other thing that is interesting and kind of give them is looking at how severe was this depression. So just to give you some numbers in a lot of the other studies. So for example, in the olanzapine fluoxetine studies, the average score on that Madras was 23 to 30 in this study. In these studies, really, they were all around 37 to 38 so that numerically, you're at least seven points higher. Seven eight points higher. So these patients were really any of the drugs approved for depression, these patients have the worst symptoms than any other study, really that's been done in terms of for FDA approval, and those patients still did well on so giving them credit, these were legitimately patients with severe depression who did well on the drug. And so that is that's a huge deal.

Speaker 2  18:56
Something happened with the blinding, however, so you mentioned that the delivery of the esketamine was through intranasal spray, but then how were they able to differentiate the placebo?

Speaker 1  19:08
The thing about is, when talking the adverse effects, this is a you know, notably, can produce that dissociative effect some of those that K hole we talked about. And so one of the concerns has been in, how do you blind this? And they used a bittering agent in the placebo. But still, there's the the idea that it would have been very likely for patients to know. So if you imagine you were in the discontinuation study, you were on this medication, this oral medication, plus you were on esketamine, you did well on that drug. You know how it made you feel. And now you're randomized to placebo or to the esketamine, but you may know that effect it gave me made me feel weird. I don't feel that way anymore. I may not be on the active drug group. And so there could have been a little bit of a factor of the fear of that, or knowing that I'm not on the active drug. Oh, my goodness, I don't have that drug that worked. Well, what's going to happen to me? And so. May there may have been a self fulfilling prophecy there.

Dr. Sean Kane  20:02
What are some of those effects that you might notice if you're taking s ketamine that would have unblinded some of these patients, or what you might counsel a patient on if they're filling this medication?

Speaker 1  20:11
So there's a number of them, and they're interesting in some of them are unusual, and some of them very high amount. So dizziness/vertigo: 42% (placebo 10%).

Speaker 2  20:21
And then I believe, just like ketamine, dissociation: 39% (placebo 19%). Yeah, really

Speaker 1  20:31
within that first hour of administration. So you notice that? You notice it pretty rapidly, yeah, nausea, 29% again, placebo, around 10% sedation, 21% some patients, it was severe, severe. So in fact, there were a couple of patients who would not even respond to a painful stimuli. So if you're doing GCs or some other rating, there is, it was not just, not just to say, like this, this may make you a little bit groggy, but for some individuals, it was pretty they did. They did say, well, it resolves within six hours. And so that's gonna something that will come back and do the counseling points for this medication is it can be profound and it can last for

Dr. Sean Kane  21:06
a while, which is interesting given the half life and our experience with ketamine, even at unless you give a ridiculous dose, which these were not ridiculous doses, really, that ketamine should be gone, well, gone within a half hour, an hour based on the dose that you give. So it's a little bit surprising that it there'd be that sedated for that long a period of time? Yeah.

Speaker 1  21:23
And so that's, I said, it's gonna be something when we talk about it, it's you gotta make patients aware. Other one changes in sensation, hypoesthesia, 16% paresthesia, 14 blood pressure increase about 10% versus 3% but one thing to look at in the data, in the package insert, eight to 17% of patients experience at least one episode of systolic increase by 40 or diastolic by 25 once within 1.5 hours of administration within the first four weeks. And so it is important to know again, is when we talk blood pressure changes. You know, we counsel on the SNRIs, so venlafaxine and duloxetine, that they may cause a 3–6 mmHg increase, but there is a subset of the population that may see a 40 mmHg systolic increase, and that is noteworthy,

Speaker 2  22:11
yeah, especially for someone like me who is managing, you know, blood pressure and outpatient setting, if, if this intranasal spray is really given in A specialty clinic, because I believe it has to be given in in front of a trained healthcare provider. If the dose is not documented, there is no way for the other providers to know that patient is on a medication that could be increasing their blood pressure and that can result into unnecessary medication changes.

Dr. Sean Kane  22:36
So Dr. Schuman, along with dizziness and vertigo, usually comes another fun side effect of vomiting. So yeah, I assume that happened as well.

Speaker 1  22:44
Yeah, again, about 10% versus 2% placebo. Concern for aspiration, given the sedation piece. But fortunately, that wasn't noted in the studies. Dry mouth noted. And then I'm gonna hit you all with one that kind of out of the ordinary cystitis, suspected cystitis at four times the placebo rate, 8% (placebo 2%)

Dr. Sean Kane  22:59
and I will tell you that this is actually something that does happen with chronic ketamine abuse, recreational abuse. This is a concern in plenty of case reports with this, with ketamine as well.

Speaker 1  23:10
Yeah, and so again, even in some cases, people needing a surgical removal of the bladder. Again, that to say that's in the the recreational use, obviously that's a more consistent, sustained use at totally different doses, apart from medical recommendations, but is to let, to let people know that there are some surprising effects. The good things, though, is a couple of the other concerns. So it has not seemed to cause any kind of cognitive impairment. We do know that the idea that, since it is blocking NMDA and increasing AMPA or adjusting with glutamate, there is the potential, if you too much excitatory stimulation leads to excitotoxicity. Fortunately, though, ketamine abuse has been seen to lead to MRI abnormalities, nothing like that has been seen in esketamine studies. And how long were those s ketamine studies? So again, we're talking, I believe these. We're still talking four week studies, but within there, they did not notice any kind of concerns,

Dr. Sean Kane  24:02
at least for me again, in thinking about how long would it take to see those MRI abnormalities, I would assume that that would not be a four week thing. That would be a year or two plus year thing. Again, making me wonder, like, did the FDA really need to improve the drug at this stage, or would they have really needed to see a longer term exposure of the drug to make sure that this is not a common side effect. Yeah.

Speaker 1  24:24
So actually, one thing to say about it is we do actually have a little bit longer data too. Even though those initial studies were four weeks, we also have data from the discontinuation study, where they continued to evaluate the patients for up to 52 weeks. And so we do have that data to show that the MRI numbers were not concerning for cognitive impairment. So that is one good thing about it. Again, we don't, you know past a year, maybe we still don't, we still don't know, but we do have a little bit of longer term data. And unfortunately, no acute liver injury; abuse potential is going to be something to note. And so again, this is a medication that is not dispensed to the patient. This is a medication that's administered to the patient in a clinic, kind of like an infusion clinic, but it's not an infusion,

Speaker 2  25:07
so on a federal schedule level, it's a schedule three drug, correct?

Speaker 1  25:11
And so yeah, dosing at first is complex and probably not convenient for the patient, at least initially, that's something to be aware of. You've got that initial dose, 56 milligrams. From there, it can go up to 84 it needs to be twice weekly for four weeks. At that point, you can decrease it to once a week for another four weeks. And then from there, you can go to every two weeks. Or you can keep going with weekly dosing. The real goal there is what's the longest frequency, or the, you know, least frequent, we can give it to still maintain patients at the appropriate dose. And there is data that the cumulative dosing is effective, it can be a good thing, but at the same time, you still need to be on that medication longer‑term. So this is not one that you know you can really stop again, just like the data show, so that you would still need to be on this one in that weekly or two, or every two weeks for as long as you want to be on the medication.

Speaker 2  25:58
Are there any particular dosing issues in terms of how to use the spray, and you know, particular administration instruction that one needs to follow, yeah.

Speaker 1  26:09
So that being said, this spray really only delivers 14 milligrams per dose given as one dose in each nostril, 28 milligrams total. So you really to give a 56 milligram dose, you got to give one dose in each nostril, wait five minutes, then repeat. And for an 84 milligram dose, you've got to use three devices with five minutes between each one, spray, spray, wait five minutes. Spray, spray, wait five minutes. Spray, spray, wait five minutes, and then do your monitoring. And the other things too is you've got to blow your nose beforehand. You can't have had really anything to eat for two hours before or anything to drink 30 minutes before, again, because of how severe that Nausea is, and they also want to make sure no oral decongestants or nasal corticosteroids within an hour again to impact the absorption of it.

Dr. Sean Kane  26:50
So at some point it seems like we've lost some of the convenience of avoiding parenteral dosing for this right? So instead of giving an im injection or an IV infusion, potentially a patient has some inconvenience now of dealing with potentially erratic nasal absorption, having to wait five minutes and dose multiple times. The kind of upside to that, though, is that this is being done, you know, once every two weeks. So it's not like this is an everyday thing walking into a clinic every single day. So I can see both an upside and the downside to this?

Speaker 1  27:21
Yeah, there's a few more complexities to it. I already mentioned about the blood pressure part. Ideally it should be less than 140, over 90 before you even give the patient the medication. So patient comes in for the medication that day, you need to really go ahead and get their baseline blood pressure. If it's greater than that, they don't say don't give it, but they say you need to carefully consider the risk versus benefit. So that kind of allows for a little bit of you know, the companies say we didn't recommend it, but if you feel the risk, the benefit outweighs the risk, you can do that. But I would say, ideally, most clinics, I imagine, are going to have a pretty hard stop of 140 over 90. But if their blood pressure is stable, risk of nausea has been attenuated by keeping them in a fasting state. They haven't any food. In 30 minutes, it's time to get the devices out. And so it's it's kind of cool. Each device has two green lights on it, one for each dose. So you hand the dose to the patient. It has the a couple grips, and it even has a little place where they can place their thumb on it. And without priming, this is another one. You prime it, you lose the dose. And as we'll see at the end, that is an expensive loss, right there. Patient leans back their head 45 degrees, they insert the tip of it into the nostril, and there's even a little little nose rest. And so you notice when that nose rest pushes right up against the bottom of the nose. That means you put put it in for far enough close the other nostril, breathe in while pushing the plunger in all the way, sniff gently. There you go, switch hands and do the other nostril. Then at that point, the provider takes the discarded device, looks at it. Both green lights should be out, one green light blinks off, and you get one dose. One green light blinks off of the other dose. Patient rests. They shouldn't blow their nose. They can dab it if the liquid drops out, some of the bioavailability piece. After five minutes again, you can repeat your doses. And then you got to observe them for at least two hours.

Speaker 2  29:01
And I'm totally adding this in my next patient counseling competition case, because this itself could be a 15 minute instruction, not for the patient, but even for the providers, how to use it.

Speaker 1  29:12
Yeah, and it's going to be, I think, because it can have some, some big issues if you don't do it.

Dr. Sean Kane  29:17
So you know, in terms of, let's say you're getting that 84 milligram dose, and you're going to be waiting up to 15 minutes. Are you dissociated at the point where you're getting that third dose, where you can't give it to yourself? Or are these patients not to the point where they are altered enough that they would be non functional in terms of re administering the dose?

Speaker 1  29:37
I believe that it's still going to be in another 2030, minutes, hopefully. You know, if it does occur to be a little to be a little bit further on, but that's something you do have to monitor the patient for, is to see. And as I said, if there is a patient that's at risk of that, to be very careful about giving them the medication because of that

Speaker 2  29:53
potential triggering effect. So what's the observation period? Are they recommending? The first thing

Speaker 1  29:57
you have to do is observe them for two hours. I. That for that two hours you really had, the 40 minute mark or so is where you need to reassess their blood pressure, and then you're and then from there, it's kind of as clinically warranted, until it's trending down, if it's trending down. And after that two hour point, is the patient still stable again, at that point, like Doctor, if they're not severely sedated or dissociated, so you know, asking them questions commands, maybe you do need to do a sternal rub. I really hope you don't need to get to that point. But as long as they're not severely sedated or dissociating at the two hour mark, you can discharge the patient. But if they're not, if the blood pressure is still holding high, maybe it's still spiking or fluctuating, you still need to keep monitoring them, and even if they do leave no driving or operating heavy machinery until they wake the next day, right?

Speaker 2  30:43
So they need to bring somebody, or they need to have a caravan to drive them home, or something like that, right, right?

Speaker 1  30:48
And so bear in mind, this whole process has to happen twice weekly during the first four weeks, so the average working adult is going to have some difficulty finding the time to devote to the treatment regimen, especially if you don't have you know someone you know. And again, you think individuals at risk for depression who may not have that social support around them may be the very ones who need to do it to come in, but don't have anyone to drive them. And so that may be another limiting factor.

Dr. Sean Kane  31:12
So Dr. Schuman, there's a lot going on here in terms of very close monitoring. Risk of patients being deeply sedated, this risk of hypertension and its implications for cardiovascular risk down the road. I would imagine that the FDA was pretty generous with the amount of Warnings and Precautions that they slapped onto the labeling of esketamine.

Speaker 1  31:31
Oh yeah, and, you know, it has a rems program. Again, it should be pretty self explanatory that it definitely has a rems program because of sedation, dissociation, abuse, liability. So again, cannot be dispensed directly to a patient. The only time the patient has any contact with it is when they hold it to put it into their nose, and then, as said, after they give the dose to give it right back to the provider who disposes of it based upon the policies of your facility for getting rid of the medication. But it must be administered in healthcare setting, you must do the two hour monitoring to assess for symptoms the patient, the healthcare facility and the pharmacy must each have separate registration that has to be done. And they're they're working at the documents to kind of help streamline that process, but yeah, that's a three separate registrations that

Speaker 2  32:10
have to occur and not to forget to fill out all the forms for DEA. Oh, yes, yes, yes, yes. And so looking from the clinic logistics perspective, it's not only a longer visit for a patient, it's a longer visit time for the clinic providers, right?

Speaker 1  32:24
So there's gonna be, there's a number of providers that have to be involved in the, you know, having the adequate staff to be able to do the monitoring. And then, unfortunately, then there's the cost itself for the medication. So the average wholesale price at this time, looking at about 600 to $900 per treatment, which unfortunately is about seven grand the first month because that twice a weekly administration, and then if a patient's still weekly or on a 14 day but every 14 day basis, you're still looking at maybe 1200 to $4,000 a month for that maintenance treatment of the medication. So you have to consider that too from a

Dr. Sean Kane  32:57
health care costs. So I'm not saying it's cheap by any means, but in terms of a medication that's being administered in a clinic, in terms of it being a brand new medication for a very, very specific niche population, things have been worse in terms of drug costs, right? So not cheap, but still not extravagant either, right?

Speaker 1  33:16
And again, the fact that there's other data coming out, more with ketamine data, but looking at the suicidality piece, and there's other aspects of that rapid response piece of it that really and the fact that, again, in patients with some of the worst depressive symptoms in these clinical trials, are doing fairly well on the medication, and even in those patients who haven't responded to numerous medications, they're doing well on it that that has to be noted.

Dr. Sean Kane  33:43
So Dr. Schuman, really interesting topic, brand new medication. You know, we're going to likely going to see more of ES ketamine as potentially more studies come out, maybe they're going to start looking at more patient populations, as you mentioned, I've already heard about and seen ketamine infusion clinics, that maybe we'll start being replaced by es ketamine administration clinics.

Speaker 1  34:04
That's the kind of the word I've heard so far. And the thing about it is, is to kind of tell it as a story is, this is the culmination with ES ketamine of years and years of research in the role of glutamate receptor antagonists in depression management, whether it's you know, medications, like you know, Memantine, or a man sitting, or, he said, ketamine infusion, but to end up finally with the first medication that has that approval. It's again, years of research and storytelling to get to this point. However, even now, we don't fully know how the thing works. It's probably has to do with the NMDA blockade and then some change in synaptoplasticity and synaptogenesis from maybe the increase in AMPA.

Speaker 2  34:43
And I think what's more staggering, as you mentioned in some of the studies, is the separation on the Madras score happen on day two versus the placebo. And that just normally doesn't happen. Like you said, in most depression studies, we talked about how your traditional anti depressions take. You know, four to six weeks for it to work. So that's probably driving a lot of optimism behind this particular agent, especially for those who are resistant on traditional agents.

Dr. Sean Kane  35:12
And as we mentioned, one of the issues with this is kind of the lack of typical data that we would see from a drug that is newly approved by the FDA. So again, recalling that some of the phase three trials were negative trials they did not show benefit, and of the two trials that did show benefit, one was a withdrawal study, where they started with ketamine, responders took away the ketamine and compared withdrawal of ketamine versus continuation of a drug that was working for you. Yeah.

Speaker 1  35:39
And then the last thing to note is some of those side effects, which can be fairly significant if they do occur, hypertension, sedation, dissociation. So because of that, it's a strict monitoring protocol, and then that need to present twice weekly for administration during the induction phase. That may limit patient acceptance of treatment. But for those patients who are candidates, and those patients who tolerate the medication again, this, this may be a game changer for them.

Dr. Sean Kane  36:02
Very interesting. Well, as I said, Dr. Schuman, I'm expecting to see more of this with commercials and as new studies come out, potentially indication creep into other areas of depression as well. So thank you for that. For the listeners, if you want to see some references, we have those available at our website, HelixTalk.com Today's episode is episode 86 we're also on Twitter at HelixTalk, where we release, over a period of several months, kind of clinical pearls from all of the episodes that we've done. So if you want to get those clinical pearls and potentially go in the Wayback Machine and listen to some of our older episodes, you can do that through our Twitter feed as well. And finally, we love the five star review and iTunes. So if you're enjoying what you're hearing, if you want to hear new episodes or new content, leave us a five star review or email us. Our contact information is on the website. We love to hear from listeners, and we want to hear from you guys about what you want to hear more of. So with that, I'm Dr. Kane, I'm Dr

Speaker 2  36:57
Schuman, and I'm Dr. Patel. And with that, study hard.

Narrator - Dr. Abel  37:01
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Narrator - ?  37:12
to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.