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 is Narrator - ? 00:12 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 160 I'm your co host. Dr. Kane, unfortunately, Dr. Patel, can't be with us today, but I am so excited to announce a special guests that we have here today. Dr. Roberta Dumais, I'll let her introduce herself, but it's so special for her to be on this podcast because she's actually an alumni of our PharmD program is now a faculty member at the college. So Dr. Dumais, would you mind introducing yourself? Speaker 1 00:55 Hi, thank you so much for having me again. I am faculty here at RFU, and I graduated way back in 2017 from our program, working with the college now as a clinical pharmacist and clinical faculty. And my clinical site is at the North Chicago VA, and I specialize in psychiatric pharmacy currently covering our inpatient psychiatric unit there. Thank you so much for having me Dr. Sean Kane 01:17 so Dr. Dumais, we brought you on to the episode because the title of today's episode is dextromethorphan for depression, analyzing data for Auvelity and major depressive disorder. So we're talking about a new drug called brand name Auvelity, which is a combination of dextromethorphan and Bupropion. And it's not what you think when I started learning about this new medication, Dr. Dumais, I thought all of the magic was in that Bupropion. But as we'll talk about, that dextromethorphan is actually doing something really surprising that we'll get into. Well, let's start with kind of a probably very typical patient case that maybe you wouldn't see in a kind of a psych unit, but you probably would see in more of a primary care type clinic. So we'll say DM is a 29 year old man who comes to his prescriber asking for a new antidepressant that he saw on TV called Auvelity. He currently takes Zoloft (sertraline), 100 milligrams a day. He's seen a therapist for depression, but despite doing these things, the sertraline and cognitive behavioral therapy for the past month, he hasn't really seen much of a change in his depressive symptoms. The question we're going to answer today is, would Auvelity be a good option for this patient? So, Dr. Duma, why don't you get us started just what exactly is Auvelity? We mentioned it's dextromethorphan and Bupropion. Walk us through a little bit of what that entails. Speaker 1 02:35 So this is a combination medication not typically seen for antidepressants. Typically we just have, you know, monotherapy, 111, type of active ingredient. This medication, Auvelity, is a combination of an over the counter cough suppressant, dextromethorphan, we all are very familiar with that. Plus Bupropion is a dopamine and norepinephrine reuptake inhibitor, a very commonly used first line option antidepressant by itself, but it's also used for smoking cessation as well. Auvelity was actually recently approved in 2022 to be used for major depressive disorder. So this added component, dextromethorphan, is kind of like the new product that we're working with here. It is also formulated as an extended release tablet. So what it actually includes is 45 milligrams of dextromethorphan and 105 milligrams of Bupropion. And because it's extended release, can't really crush it, divide it or chew it. Dr. Sean Kane 03:34 So Dr. Dumais, what's so cool about this combination is that we're actually intentionally causing a drug interaction. And you might think, well, it's got Bupropion. That's the magic here. But actually, we don't think that's the case. So if we just go to Bupropion, intuitively, you would associate it with its antidepressant quality, again, the dopamine, norepinephrine reuptake inhibition. But in reality, it's not necessarily there for that, is it? So what is it doing as part of this combination. Speaker 1 04:01 So what is actually happening is that Bupropion is inhibiting dextromethorphan by the pathway of CYP2D6, which is a very common CYP enzyme responsible for the metabolism of a lot of antidepressants, and Bupropion is one of them. So what happens here is that dextromethorphan is metabolized via this pathway. So therefore, by incorporating or adding Bupropion, we are inhibiting the dextromethorphan metabolism, therefore increasing dextromethorphan level drug levels in the body. Another thing to kind of keep in mind of is that the active metabolite of dextromethorphan, which is called dextrorphan, is responsible for some dissociative effects that we associate you know, that we may know from pop culture with dextromethorphan misuse on the market. Dr. Sean Kane 04:51 So Dr. Duma, just to be clear, what you're saying is that the Bupropion here is being used as a CYP inhibitor to make it so that dextromethorphan isn't as readily metabolized. So we're going to get higher dextromethorphan levels, and it's going to be harder for the body to produce this metabolite, dextrorphan. But kind of going back to the original question, why do we want to have higher dextromethorphan levels? What benefit could that potentially provide, aside from a cost perspective, it doesn't seem like that's what we want in this condition, right? Speaker 1 05:21 So what does dextromethorphan have to do with mood, right? It's interesting because this is a newer pathway that we're looking into. Dextromethorphan utilizes a pathway that's the NMDA receptor. It's an antagonist of the NMDA receptor, and it also is an agonist of the sigma one receptor. So again, this is a newer pathway, you know, not just looking at our monoamine pathways that we typically know are familiar with with antidepressants. Dr. Sean Kane 05:50 And just for clarity, that sigma one receptor, we think that that is what is involved in the cough suppressant quality of dextromethorphan. So really, the NMDA is something that we haven't historically been that interested in, but we think that might be the magic here. Exactly. So. Dr. Dumais, it's great that we have a new agent on the market. The other thing that came to my mind is, do we need one? You know, we have a number of antidepressants already on the market. As you mentioned, most of those are looking at kind of the monoamine pathway where they're increasing, mostly serotonin, but some of them dopamine, norepinephrine, sometimes a combination of different ones. Do we need a new one? Are the current ones leaving something to be desired? Speaker 1 06:31 That is always a great question. And as you can see with recent medications that may or may not have come out, there's always an opportunity to provide more options for patients, especially those who may have failed all the first line options. If you look at our landmark study trial, two thirds of patients didn't achieve remission with first line treatments, and in that case, they were looking at citalopram. So there is, it seems to be that there is an opportunity for more options, or at least different pathways, because a lot of these options that we've talked about all do have that same pathway. And now we're introducing a potentially new pathway with this NMDA receptor pathway. Dr. Sean Kane 07:09 And then the other thing related to that star d trial that most pharmacy students learn when they learn about depression is that those SSRIs a sunrise and TCAS, all of those monoamine pathway oriented drugs, they take many weeks to really reach full potential, like six to eight weeks, right? Speaker 1 07:28 Yeah, so it's that's something that is kind of like the bread and butter of when it comes to our counseling, is how all antidepressants take at least four to six weeks to start seeing benefit in depressed mood, in kind of like hopelessness. They may feel like, you know, very short term effects of like, better sleep quality, things like that early on. But it's not only is it not all of them effective, but they do take a while to really start working to help with the depression. Dr. Sean Kane 07:55 And you mentioned that the NMDA receptor, which for those going back to kind of physiology. Glutamate is the ligand that activates the NMDA receptor. This is typically like an activating type receptor. You mentioned that this is kind of the new hotness in terms of antidepressant drug therapy. Do we have other drugs that have looked at NMDA blockade in some way? Speaker 1 08:16 Yeah, for depression, in particular, ketamine or s ketamine is a recently approved medication that is used for treatment resistant depression or refractory depression. The esketamine is the nasal spray version, and it is actually mentioned in a previous HelixTalk Podcast, episode number 96 so it's, you know, something that is definitely on the market and continuing to look into that pathway. Dr. Sean Kane 08:41 And as we mentioned, that same pathway, we think is what is happening with dextromethorphan by inhibiting its metabolism, and we can keep it around longer, as opposed to the metabolite of that dextromethorphan. We think that that may be the magic here when it comes to a velity, in terms of extending that parent drug of dextromethorphan, which is an NMDA receptor antagonist, right? Exactly. Okay. Well, how do we dose this new antidepressant called obelity? Speaker 1 09:10 It's an interesting medication. It's dosed one tablet daily, and then after three days, it goes to one tablet twice a day. The max target dose for this medication for this medication, Auvelity, is 90 milligrams of dextromethorphan and 210 milligrams of Bupropion per day. And just as a context, it may seem like you know you're questioning this dose a little bit the Bupropion component, typical dosing that we see for major depressive disorder can be upwards of 300 to 450 milligrams a day as maintenance. So that 210 milligram for the starting dose is a little bit on the low end, which is interesting. And on the flip side, for the dextromethorphan dosing as a cough suppressant, it's 120 milligrams per day. So this is more or less aligned with what we usually see for OTC dosing of dextromethorphan. So. Dr. Sean Kane 10:00 And Dr. Duma, I think that's important, because when we look at other drug interactions, and ritonavir is probably a really good example of this, with paxlovid, oftentimes, when we use a drug as a drug interactor on purpose, where we're kind of boosting an HIV regimen or paxlovid or something like that, usually the drug interactor the dose, is typically a sub therapeutic dose. So when we use ritonavir, that dose is not an antiviral dose, it's just a drug interactor dose. But in this case with Bupropion, it is on the lower end, but it's still, I would call it a therapeutic dose of Bupropion, in the sense of, it's enough that you're going to get that dopamine, norepinephrine re uptake, inhibition. It's not going to be to the extent of, kind of the maximum dose, but you're still getting, like a realistic Bupropion dose here. Correct? That is very true. Correct. Okay, you know, one, one question that came to my mind is, how big of a drug interaction is this, right? So I get that it's causing a drug interaction. Is this kind of voodoo medicine, or do we actually see that we're truly increasing dextromethorphan levels in the blood and avoiding that metabolite that is associated with some of the euphoric effects the patients may experience when they abuse dextromethorphan. Speaker 1 11:09 There isn't really too much in the products labeling, as far as like the kinetic data on this particular drug interaction, I think digging way back at looking at a 2005 article they did compare dextromethorphan metabolism with Bupropion, 300 milligrams per day versus placebo. And what they found was that with the placebo, the amount of urinary dextrorphan, which is that active metabolite that we mentioned previously responsible for like the euphoric feeling or the misuse of dextromethorphan to the dextromethorphan parent drug was about 80 to one, which means that most of it was the metabolite in the in the urine, and looking at this would be propioned, the ratio was about two to one, so still seeing more dextrorphan, that active metabolite, but much, much More parent drug with this combination of the two medications, Dr. Sean Kane 12:03 and that's a pretty big difference, that the ratio goes from 80 to one in the urine to two to one in the urine. In effect, you have much, much more dextromethorphan that you're excreting that never got metabolized. As opposed to, if you don't have that drug interaction, the vast majority of the dextromethorphans getting metabolized to that active compound. Speaker 1 12:21 It's really quite elegant and a perfect example of like a drug, drug interaction. So it I get very excited about seeing this kind of data. Dr. Sean Kane 12:28 Intrinsically, I wanted to know, Okay, that's great that you pee out more of the parent drug that never gets metabolized. There are actually other studies out there that looked at blood levels of dextromethorphan, not with Bupropion, but with other CYP2D6 inhibitors, Quinidine is the typical example here. And with Quinidine, which may be a slightly more potent CYP inhibitor, what we saw was dextromethorphan levels went up by about 10 to 20 times. That is a lot of drug interaction there. That is definitely true. So clearly CYP2D6 is important for this Auvelity drug to work, where we're blocking that pathway. But at least when I learned about pharmacogenomics, I learned that 2D6 is like a mess when it comes to how different human beings use the 2D6 pathway. Can you kind of enlighten us in terms of how weird this pathway is, and how unpredictable it is when it comes to human beings. Speaker 1 13:25 Yeah, so CYP2D6 is definitely a SIP enzyme that there's a lot of interpersonal variability with their pharmacogenomics in terms of like how they metabolize medications that use this pathway. So looking at activity scores, which is kind of like a categorization of somebody's ability to metabolize you could have somebody who is an ultrarapid metabolizer of CYP2D6, so their activity score would be greater than two so they quickly metabolize medications that can utilize this pathway, those who have normal CYP2D6 metabolism or previously, they were called extensive metabolizers. And there's also intermediate metabolizers, so that, let's say they're below normal. But then they, then there's the last option, which is a poor metabolizer. So they, you know, do not metabolize medications that utilize this pathway. Dr. Sean Kane 14:20 And what's interesting Dr. Dumais about this pathway, clearly, Bupropion works on this pathway to inhibit it, and dextromethorphan uses the pathway. But in your neck of the woods, CYP2D6 phenotypes are actually kind of relevant in terms of some of the drugs that you typically see in your practice, right? Speaker 1 14:36 Yeah, while it may be, not be standard practice to utilize pharmacogenomic testing for people who take psychotropic medications. I think it is the way of the future, and it is definitely common with a large variety of antidepressants and some that we've already talked about in this episode, including certain tricyclic antidepressants or TCAS SSRIs, which is a first. Line option that we use to treat depression and even some antipsychotics. So what we're dealing with here is, if somebody has less activity or lower metabolism, you're seeing higher drug concentrations. And you know, maybe they don't tolerate starting doses of these medications. Just as an example, Dr. Sean Kane 15:18 and I love this pathway in my neck of the woods, because many opioids are activated to a more potent opioid form using CYP2D6. So codeine is a typical example here where someone who's an ultra rapid metabolizer, they do a really, really good job of converting codeine, which is a weak analgesic, into morphine. The body literally makes morphine from codeine, and they might make a ton of morphine if they're an ultra rapid metabolizer, and they could get over sedated, or have some of the bad side effects that are dose dependent, side effects of codeine. Or if someone is a poor metabolizer and they don't activate codeine very well, they may take codeine and say, this is drunk. It doesn't work at all because their body is lazy and doesn't make any morphine, right? It's so crazy how different drugs are going to act differently in different patients, and that's why this 2D6 pathway is so interesting with Auvelity. Because, as we'll talk about in the studies, they didn't do 2D6 genomic testing on the patients. We don't know whether these were people who are more likely to have normal or ultra rapid or poor CYP2D6 metabolism type pathways. So what are your thoughts in terms of how genomics may play a role in the efficacy or safety of Auvelity? Speaker 1 16:31 Yeah, so across the board, and with Auvelity in particular, doing pharmacogenomic testing is not part of, you know, starting a medication. However, I did actually take a look at the drug monograph for Auvelity. And they actually do have a recommendation for somebody who is a known poor CYP2D6 metabolizer. They say to start at the starting dose of one tablet in the morning and and just keep it at that dose instead of increasing it to twice a day dosing after three days. So that's already in the monograph. So they, I think, are aware of this particular pathway by already including it in the monograph. Dr. Sean Kane 17:05 Using that same logic, that patient who is a very poor 286 metabolizer may not need Bupropion to extend the effectiveness of dextromethorphan, or conversely, the patient who's an ultra rapid metabolizer, that Bupropion may not be enough to inhibit their pathway, and we don't know the answer to that, because it's kind of an unstudied question, but it's really interesting. As you mentioned, Dr. Dumais, we don't typically do genomic testing to start an antidepressant, but are there known examples where there are antidepressants that are working on this pathway that we should be aware of? Speaker 1 17:39 Yeah, some some antidepressants of note include fluoxetine and paroxetine. These are both classic examples of two SSRIs that are often started first line in somebody who may have never tried any antidepressants, and data shows that both of these inhibit the metabolism of dextromethorphan as well. So could this be another me too, drug in the future like a fluoxetine dextromethorphan combo. Jury's still out. Dr. Sean Kane 18:06 Time will tell. But anyone who's in the pharma industry who's listening to this, you can pay us the royalties for identifying a new opportunity here of fluoxetine plus dextromethorphan as a me too to belly. Unknown Speaker 18:19 Yeah, our contact information is attached. Dr. Sean Kane 18:22 So the other thing to note, and we see this with paxlovid, with ritonavir, we see this with many other booster type drug interactions, especially in the HIV therapy. We're using Bupropion to boost or to prevent the metabolism of dextromethorphan. But if you add Bupropion, fluoxetine, paroxetine, these drugs that block that CYP2D6 pathway, we have to keep in mind that it produces a drug interaction for any drug that goes through that CYP2D6 pathway, not just dextromethorphan, right? Speaker 1 18:51 Exactly some we may have already mentioned, but tricyclic antidepressants, antipsychotics and those opioid analgesics that you mentioned earlier, could also you know, if they are taking these concomitantly, you will see that drug interaction as well. Yeah. Dr. Sean Kane 19:07 So again, huge role for pharmacists here to identify when you are adding something like Bupropion or Auvelity or fluoxetine or whatever, you're going to have drug interactions that could impact other drugs that maybe are not your intended target of that drug interaction. Well, Dr. Dumais, you know, at this point we have two drugs in this one combination tablet of Auvelity that are already on the market. So we know lots about Bupropion. This is kind of your bread and butter now, in terms of what do we need to know, or what reminders might you tell our audience about things to know about, warnings, precautions, contraindications when it comes to mostly Bupropion, but if you have any advice about dextromethorphan, we can talk about that Speaker 1 19:48 too sure. So I think it's important to review that box warning that comes with all antidepressants, and this is regarding suicidal thoughts and suicidal behavior when especially. In those young adults. It's not specifically associated with Auvelity, but there is that box warning that's associated with Bupropion alone. So it's something to be aware of from looking at like short term studies in the pediatric and young adult population. It's usually where this comes from, just given the impulsivity of those age groups in particular when you're starting a medication like an antidepressant, because usually motivation is the first one of the first symptoms that improves, as I mentioned earlier, sleep is another one. So that's why you have that initial short term suicidal ideation in the first couple of weeks within starting another thing to be aware of, in particular with Bupropion, is the increased risk for seizures, and this is a contraindication for folks who have known seizure History Prior to taking Bupropion, and it is dose dependent. However, it can be at therapeutic or even starting doses for those who are at increased risk for seizures. So looking at this medication, those people who are prone to seizure risk or contraindicated, of course, those who have a known epilepsy or seizure history, even certain eating disorders like bulimia or anorexia nervosa, those conditions themselves, with electrolyte imbalances and being malnourished, the seizure threshold is decreased, so giving somebody a medication, ibuprofen, could potentially induce a seizure. Also those who have a history of alcohol use disorder or just heavy alcohol consumption, if they you know, suddenly stop drinking, they're at an increased risk for seizures, and combining that with a medication like Bupropion could potentially also increase that risk as well. Dr. Sean Kane 21:39 One thing that comes to my mind about Bupropion is that that seizure risk is dose dependent, and it's kind of interesting. When the drug first came out in the 1980s the max dose was actually 600 milligrams a day, but then a bunch of people had seizures at that Max dose, and they actually took it off the market temporarily and then revised the max dose to just 450 milligrams a day because of that risk, and then reintroduced it to the market. So again, we have about 200 milligrams of Bupropion in Auvelity, 210 milligrams, so it's on the lower end, but it's still enough that if someone is at very high risk of seizures, I would still avoid this medication, right? Speaker 1 22:13 Of course, of course. And you know, doing your due diligence on asking about these particular questions is important if you are deciding if Auvelity is the right fit for somebody. Dr. Sean Kane 22:23 What else do we need to worry about or precautions when it comes to bureau propion. Speaker 1 22:27 So given the its pathway via dopamine and norepinephrine, we are potentially worried about increasing or worsening high blood pressure, hypertension, you know, tachycardia. These are, you know, pathways that we know that can cause that so especially initially, somebody's blood pressure may increase or worsen. Probably a reason why Bupropion isn't really used for anxiety, because it just mimics anxiety symptoms and we use it solely for depression. So it's definitely something that to consider if somebody has pre existing hypertension to potentially avoid using this medication, Dr. Sean Kane 23:03 of course, as a critical care pharmacist. If you asked me, What does dopamine and norepinephrine do, these are literally vasopressors that we use in the ICU, right? And it's a little bit different, because we're just changing the synaptic concentrations, as opposed to giving extra of these neuro hormones. But still, like it's not that surprising that we would see some quality of hypertension, and we also see this with other drugs that work on norepinephrine, like SNRIs, like duloxetine, for example. We do see that quality because of that norepinephrine component. So again, not super surprising. But as you mentioned, something we should be aware of. We can also see some neuropsychiatric reactions with Bupropion. So you mentioned that it can worsen anxiety. Are there other things that come to your mind when it comes to kind of the side effect profile of buprenorph, Speaker 1 23:47 yeah, typical to what we we may have learned in school with all antidepressants, if somebody had is predisposed to a bipolar type of a polarity in terms of their mood, so not just strictly depression, if somebody actually has that in their history. And you give somebody this medication looking for symptoms of mania or manic symptoms, hypomania, even even going as far as delusions, hallucinations and psychosis can be a side effect of this medication. If you know we're mistreating what seems to be a depressed episode, but it's actually has a bipolarity type, and it's bipolar disorder. Dr. Sean Kane 24:25 And then in terms of the dextromethorphan, as we kind of alluded to earlier, the main concern here, not necessarily without Auvelity, but with dextromethorphan at higher doses, kind of abuse type, doses, that active metabolite that we're trying to avoid formation of using bupropion as a CYP2D6 inhibitor that actin metabolite can cause some of these neuropsychiatric reactions, potentially psychosis, but at higher doses, super coma, hyper excitability. And you know, in kind of pop culture, this is sometimes called Robo tripping. The robo comes from Robitussin that you're abusing it. You're kind of tripping in terms of having a psychiatric reaction to the medication. So this is mostly seen in overdose type scenarios, as opposed to normal therapeutic doses of dextromethorphan. We can also see potentially serotonin syndrome. Usually, this would be only when you're combining it with other serotonergic drugs. Again, Bupropion is not serotonergic, so it'd be something like an SSRI, or other medications that promote serotonin, and then also this is teratogenic. So we would avoid using Auvelity in pregnant women. So Dr. Dumais, we've kind of talked about everything they know about the medication itself. I assume that the medication get FDA approved by having randomized control trials, the kind of standard that a drug gets approved to the market, maybe we can go through some at least two of the trials that were evaluated by the FDA to get the drug approved. Yeah, let's do it. So there's two main trials. The first one was a very small phase two randomized control trial. Both of these are cited in our show notes again, HelixTalk.com episode 160 and this was Auvelity versus Bupropion, so really the only difference is adding dextromethorphan, and it was a six week double blind RCT in 80 people. So we're not gonna spend a lot of time on it because it was only 80 people, but kind of interesting, because it's really showing whether it's the Bupropion or the addition of dextromethorphan, that is really the magic here. So Dr. Duma, what did this trial show? Speaker 1 26:24 So what they found was they looked at the odd Auvelity, they found that it was superior to Bupropion alone, looking at depressive symptoms over a six week period, which actually was statistically significant already at week two, which is something that, for me, is a very interesting finding in a clinical trial, Dr. Sean Kane 26:44 and then, and we'll get more to efficacy when we talk about the larger trial called the Gemini trial, but again, big deal to have it so early, so we'll see if that kind of holds true with the larger RCT. What about safety? Did having dextromethorphan around longer and not metabolizing it as readily have any difference in side effect profile. Yeah. Speaker 1 27:04 So looking at both groups, they were equally likely to discontinue therapy due to adverse drug reactions. It was sitting at around 12% for both, for both groups, which is interesting, I guess, with the added component, I thought there would be a little bit of a higher side effect profile with the with the dextro group. But what they mainly found was dizziness was more common with Auvelity as compared to the one without the dextro. And then anxiety was also increased, which was also interesting to me, and Dr. Sean Kane 27:35 they did see numerically some other differences, but we'll get more into the larger RCT and some of the package insert data to talk about the side effect profile, and that's a good segue, really, to the Gemini trial, which was the larger phase three, not phase two, but phase three RCT. They looked at about 300 patients, as opposed to 80 patients. So this is a much larger trial, and Dr. Dumais, it always blows my mind. We still have placebo controlled trials and major depressive disorder, but for good reason, right? So this was a Auvelity versus placebo, controlled trial over six weeks. Do you want to just comment on why we're still using placebo for evaluating drug therapy and depression? Speaker 1 28:14 Yeah, it's an interesting phenomenon that we see in like major depressive drug trials, in that you know, if you do a randomized, controlled trial per protocol, patients are coming in every week or every couple weeks to get reevaluated. So that inherent bias of just coming in and having a structure and a routine is potentially therapeutic for these people. This is, you know, as much as we like to mimic real world instances, this is not necessarily how people are treated with their medication. They're not being seen weekly to get reevaluated, so that's possibly what's going on here. So we see a high placebo response because of potentially that human interaction that sometimes, I guess, is needed when treating depression. Dr. Sean Kane 28:56 Okay, so this trial included adults 18 to 65 so they were not looking at elderly patients, and these are patients with major depressive disorder that has lasted at least four weeks, and they evaluated these patients to have moderate or severe depression based on a Madras score and a CGis score. We're going to focus on the Madras score because that was their main primary endpoint. But they did use a standardized score to make sure that these patients had moderate to severe depression. Speaker 1 29:23 Patients were excluded that had treatment resistant depression, which they defined as having failed at least two or more other treatments, and those who had high risk of suicide and those who had a seizure history. Dr. Sean Kane 29:37 Dr. Duma, what was, we'll talk about a variety of endpoints, but what was their primary endpoint in this trial? Speaker 1 29:42 The primary endpoint that they looked at in this trial was a change in total Madra score, which is a 10 items scale we use for looking at severity and symptoms of depression. It's a validated scale. It's a very common scale that we see in clinical trials. If we look Dr. Sean Kane 29:57 at the results of these roughly 300 patients. Patients that were randomized to Auvelity versus placebo, their baseline Madra score was about 33 so anything more than 25 or so indicates moderate or severe depression. So that's who we're looking for. And the primary endpoint of change in that Madra score over six weeks was minus 16 points for Auvelity and then minus 12 points for placebo. So the difference was almost four different in favor of LD, and that was a significant finding. And Dr. Dumais, in your experience, what would a typical Madras reduction be in a typical antidepressant trial? Speaker 1 30:33 Typically, it's only about two to three points between drug versus placebo. Dr. Sean Kane 30:38 Okay, so difference of about four is actually pretty good in this trial, like we're pretty excited. Pretty excited about that. Is there any other reason Dr. Dumais that this was particularly exciting when it comes to the efficacy? Speaker 1 30:49 Yeah, so we kind of hinted at it earlier with the previous study. Is like the early onset of improvement in symptoms. So when you look at week one, Auvelity showed an improvement in the Madra score two points, which is a big deal because it suggests that this onset of benefit is much faster than what we typically see with medications that are on the market, first line options like SSRIs, SNRIs and TCAS, which, as we mentioned earlier, take at least six weeks to see full benefit. Dr. Sean Kane 31:20 So big deal that it worked and that it worked quickly. And we won't go into it, because there's probably 10 different ways that they looked at the efficacy of ability versus placebo, but generally speaking, almost all of the other efficacy endpoints were in favor, both clinically and statistically significant. In favor of ability. Number needed to treat for benefit was about five to 10. They also looked at remission, which they defined as a moderate score of 10 or less. At week two, they saw a difference. And Dr. Dumais you and I talked previously, it sounds like that's kind of a big deal to go to more than 25 again, the mean was 33 all the way down to less than 10. Yeah. Speaker 1 32:01 Remission rate by Week two is not something I have. It's hard for for me to wrap my head around. Typically, that would take months of, you know, current treatment that we have available to see remission rates. Dr. Sean Kane 32:13 Okay, so kind of big deal. They looked at clinical response of that Madras score going down by more than half. They looked at other depression scales, like the CGis, all of these generally were in favor of Auvelity, and we won't go into those details. What about safety? So we now have more patients in our phase two trial, so maybe we can look at safety a little bit in more detail. Dr. Duma, what kind of safety profile did we see versus placebo? Yeah. Speaker 1 32:38 So what we found were that patients were more likely to stop Auvelity as compared to placebo, which was significant mostly due to dizziness, nausea, headache, diarrhea, dry mouth, sweating, very like hallmark symptoms as side effects of dextromethorphan, which is makes sense, there were no psychometric effects that were seen like when you think of a medication like ketamine and looking at the NMDA antagonistic effects, no sexual dysfunction, no weight gain, which is a typical kind of like Plus, when we are prescribing somebody be propion. Dr. Sean Kane 33:10 So again, if you go into the phase three trial, the phase two trial, and also just the package insert to highlight some of those side effects, again, these are very Hallmark side effects of dizziness, nausea, headache, diarrhea, dry mouth, and at least when I was a student, I just assumed that this was kind of background noise, that even the placebo arm had these side effects, but it was actually more common with the drug therapy versus placebo, right? So we do see these as true side effects, not just kind of junk side effects that end up in micro medics, because that's the background rate of diarrhea, for example, Speaker 1 33:45 exactly taking anything by mouth can cause something like this. Dr. Sean Kane 33:49 And we do see hyper hydrosis or sweating, which we also see with SNRIs, probably from that norepinephrine quality. And interestingly, we see kind of opposing side effects. I think it's worth highlighting just for a second. So we see somnolence at 7% versus 3% and then insomnia 4% versus 2% so Dr. Dumais, does this drug cause you to be sleepy, or does it make you have difficulty sleeping? Speaker 1 34:16 It's interesting. You got two opposing medications at work here. So when you dose Bupropion alone, it's typically an activating medication. I ask my patients to take it in the mornings. So the insomnia component could be commonly due to the Bupropion. However, dextromethorphan has a little bit of like anticholinergic activity, potentially, so the somnolence or the sleepy component could be caused by that. Dr. Sean Kane 34:40 Yeah, so clearly there's some inter patient variability going on here, which, as we alluded to earlier, could be as simple as the amount of CYP2D6 activity that a patient has because of their genetics, right? And it's not unusual. I don't think that different patients are going to respond differently to different medications. Speaker 1 34:58 Yeah, we're getting closer and closer to like. Personalized Medicine by looking at these genomic data and how it's like individualized to each person. Dr. Sean Kane 35:06 So Dr. Dumais, this is a new drug. I'm going to go out on a limb and assume that this is not $1 a day type medication, right, exactly. Speaker 1 35:15 So this is a newer medication that just got approved last year. So we're looking at $21 per tablet needs to be taken twice a day. So the the math whizzes identified that it could be upwards of $1,300 per month for taking this medication. And even Dr. Sean Kane 35:33 if you look at like a good RX, you're looking at about $1,000 per month. So this is not an inexpensive medication. But obviously, if you have coupon or if you have prescription drug insurance that covers it, the cost is going to be lower. This would be without insurance, kind of the cash price. So the logical question that I had in my mind, Dr. Dumais is, okay, we have dextromethorphan that's already on the market. We have Bupropion that's already on the market. Can I make a DIY version of ability where I just take those two medications separately, as opposed to paying $1,000 a month for ability as a cash price. Speaker 1 36:08 So the kinetic profiles of taking these two separately will definitely be different than when they were in the combined formulation in Auvelity, and we don't know how these will change the effectiveness of taking this combination. So when you look at it, Bupropion is already available as an antidepressant. It is readily affordable. It's typically on the formulary list for most insurances, depending on which formulation to you take. It's available as an SR, an ER and excel tablets. It can be taken one to two times per day, and then the 100 milligram tablets is available for around less than $10 per month. So by taking just the 100 milligram tablets, which is already available, you would be missing on extra five milligrams. So that extra five milligrams, by trying to create this on your own, will it be less effective, maybe, maybe not. Dr. Sean Kane 37:02 And I feel like the five milligram extra Bupropion that they put in here was just kind of a poke in the ribs to anyone trying to make their own Auvelity. DIY version, just to make it a little bit different than what was commercially available in terms of the dextromethorphan, as I mentioned, it's a cough suppressant, any solid dosage form where you take it as a tablet, capsule, something like that. Those are all immediate release and you have to take them, you know, every four, six or every eight hours. So most people are not going to do that. We do have an extended release formulation, but it's a suspension brand name is del sum, and there's a variety of kind of off brand products out there. So a patient could do that, where they take their SR Bupropion, and then they take their del sum, or off brand del sum er suspension, but they're going to have to take 15 mls of that twice a day, and that's about three bottles worth, which would be about $45 a month. So yes, you could technically do this. The problem, though, is that you're going to be buying three bottles of delsam a month. You're going to have to have the bottles with you twice a day. Doesn't really fit in your pocket, and it's not exactly what was studied. So sure it's possible, but I would say not convenient, not how it was studied. It would make me a little nervous to go this pathway and Speaker 1 38:11 you have to drink delsam daily, which doesn't sound fun at all. Dr. Sean Kane 38:15 Probably not so. Dr. Dumais, in your professional opinion, what is the place in therapy of a valid at this point, granted that it's a brand new drug and things like that, Speaker 1 38:26 so looking at the at this medication cost is always a driving force of choosing this so it's definitely going to be more cost prohibitive as compared to other first line options. As mentioned earlier. There could be some good RX coupons, but the manufacturer does also offer a savings card, you know, so understanding if you qualify for that, you know, looking at commercial payers, if you have insurance, if you don't have insurance, it can only probably be used once looking at like, kind of like the fine detail there we mentioned already, the DIY Auvelity option, but it's not practical. And so because Auvelity is so new, it's also not discussed in guidelines. And a lot of you know our recommendations are guideline driven, looking more into some recent guidelines. The American Psychiatric Association came out with an updated 2019, depression guidelines, and they continue to recommend SSRIs, SNRIs, as as first line options, which is interesting because they don't mention Bupropion, despite it being used first line in clinical practice everywhere. Other guidelines, like the VA DoD depression guidelines that were recently updated in 2022 list a couple of added options, aside from SSRIs and SNRIs, and it does include Bupropion, where tazapine Trazodone and some other newer antidepressants like velocidone and 40 oxidine. They do discuss that Bupropion is a good option, and those who also may have that added kind of comorbidity of tobacco use disorder and they want to quit smoking and it also has the less sex. Side effects that other first line options have, namely SSRIs and SNRIs. And as Dr. Sean Kane 40:06 you mentioned earlier, Dr. Dumais, one of the big deals with that phase three trial was the fact that it works so quickly. So if there's some reason that you want it to work quicker in a patient, which typically you do anyway, but if there's some compelling reason, maybe this might be something you consider a little earlier? What do you think? Speaker 1 40:22 Yeah, I definitely would be curious to try this in somebody who probably has had little to no efficacy with some of these other options and are at their wit's end to seeing some results sooner. Dr. Sean Kane 40:35 And what a great segue back to our patient, case of DM. He was our 29 year old. He's been on sertraline, 100 milligrams, and psychotherapy for about a month. It's not working. What are your thoughts for that patient? He's asking about a validity because he saw a commercial or an ad or some direct to consumer advertising, about a validity. Speaker 1 40:54 So some things to first kind of talk about with DM is it's important to kind of see where he is in his current therapy. He's only been on it for about a month, so we are still probably on the early stages of seeing its true benefits stopping. Now we could potentially kind of hinder identifying if Sertraline is going to be helpful if we just wait another month or so. I guess up to eight weeks total is when I would give a medication its fair trial and seeing if it was effective for that particular patient. So we have to kind of look at his severity of his symptoms. It could be reasonable to wait another month, or it could not. And there's also the potential for he's tolerating the current dose. There's room to go up. Max doses of sertraline are typically 200 milligrams per day. He's only at 100 so we can definitely titrate the medication for him. Dr. Sean Kane 41:44 Cost is going to be the other thing to talk with the patient about, and it's going to be more expensive, and there are a number of other antidepressants that are cheaper, better studied, that maybe are better options for him, regardless of his desire to use Auvelity. Keep in mind that we really only have one larger randomized control trial of Auvelity, and it was a six week trial. We have so many other options, like a different SSRI, an SNRI, just choosing Bupropion period, I could go on and on, and this is definitely not my area of expertise. But would you agree that Auvelity is probably not our second line option for this patient? Speaker 1 42:19 I definitely want to exhaust some other options that are more affordable to DM before jumping to Auvelity for sure. Dr. Sean Kane 42:26 So Dr. Dumais, I think that kind of wraps up today's episode on Auvelity quite nicely, just to kind of reiterate some key points here. So Auvelity is a combination product of Bupropion and dextromethorphan. It was FDA approved in 2022 for major depressive disorder. And the way it works is that that Bupropion is inhibiting CYP2D6 metabolism and increasing concentration of dextromethorphan. And we think by having more dextromethorphan and prohibiting or reducing amount of metabolism, we have it work as an NMDA receptor antagonist that may have some magic in depression. Speaker 1 43:00 And all the Bupropion component of Auvelity is being used for its drug interaction. The dose of Bupropion itself is a therapeutic dose, and should be mindful that it carries those several Warnings and Precautions like seizures and hypertension. Dr. Sean Kane 43:16 And then we mentioned the the main trial, the Gemini trial, which is cited in our show notes. It was a six week RCT, and the big notes of that is that it worked really, really fast, within one to two weeks, way faster than traditional antidepressants. And it does have some side effects, like dizziness was the big one, but we also can potentially see anxiety, sweating, nausea, headache, diarrhea, dry mouth, among a number of other side effects that are kind of these non specific side effects associated with many other antidepressants as well, Speaker 1 43:45 exactly and as a CYP2D6 inhibitor, the Bupropion component of Auvelity can cause drug interactions with other medications, not just dextromethorphan, which includes some antidepressants, certain antipsychotics and even opioid analgesics, among others. Dr. Sean Kane 44:03 So for the listeners, if you want to dive into the Gemini trial or look at any of the references about the pharmacokinetic data of this drug interaction, we have all of those in our show notes. It's at our website, HelixTalk.com, and again, this is episode 160, we're also on Twitter at HelixTalk. We love the five star reviews in iTunes. We have a mailing list, and you can sign up at our website, HelixTalk.com and again, I wanted to give a special thank you to Dr. Dumais for joining us today and providing her wonderful expertise on the topic. Speaker 1 44:33 Thank you so much for having me, Dr. Kane, and in the words of Dr. Patel, study hard. Narrator - Dr. Abel 44:39 If you enjoyed the show. Please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 44:50 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.