A New Long-Acting Injectable: Olanzapine (Zyprexa) Weltruza

This podcast provides general information, not a substitute for professional medical advice. Please consult your physician for personalized guidance. Hello, hello, welcome back to PsychRounds, a resident-run educational psychiatrist podcast. I'm Dr. Tanner Hewitt, joined by my co-host, Dr. Larry Wang, and Dr. Bradley Miller. Now, today we're going to be talking about a very recent and potentially very significant development in psychiatry. So specifically, I'm referring to the FDA approval of a new long-acting injectable, a Lanzapine Welchruza, which was approved October 9th of 2026, made by the company to have a pharmaceuticals. Now, as usual with new developments, we want to emphasize to our listeners that we do not have any conflicts of interest nor receiving money from any pharmaceutical companies. Now, this development is something that we've been following a few years now. As if you listened to our original Lanzapine episode back in 2024, you'd note that we mentioned the early promising results of the Solaris trial and even remarked by saying, "Who knows? Maybe we'll have another Lanzapine LAI in the market in a few years." Hopefully, well, it's here now, two years later, and this may not be a meaningful edition for our psycho-pharmacology armory, if you will, our bucket of tools, if you will. But in proper context, we plan on briefly reviewing both the original medication Lanzapine or branded asiprexa, as you may know, as well as the history of its long-acting injectables, like RELPREV, another LAI that came out with an unfortunate side effect, and then transitioned to the significance of this new approval with, well, Trusa. So let's get into it. So we'll stay as an inpatient psychiatrist currently. This is something I've been waiting for for a few years, been following the Solaris trial pretty closely, and the three of us have a group chat. I think a couple of Fridays ago, Tanner posted this FDA approval in the group chat, and I responded by saying something along the lines of, you know, this might be one of the most significant psycho-pharm developments in the last few years. And I do want to disclose before we get started that somehow already a couple of drug wraps have visited the hospital I work at, and have presented some educational materials. But for those worried about my integrity, I definitely didn't receive any money, and they didn't even bring any food, so I didn't get a burger. I got literally zero material benefit, just some information and small talk. Alright, so let's start reviewing the base medication of Lanzapine, also known as Zyprexa. And also, I guess, as a general note here before we dive in too much, this is still very new. There's no post-marketing surveillance here. There's no personal experience from us, or probably like hardly anyone in perscribing this medication. But when it comes to Zyprexa, we had an entire episode dedicated to this in November 2024. It's about 20 minutes long, if you're interested, go check it out. But I imagine there are some audience members who would appreciate a shorter summary. So here we go. Lanzapine was an FDA-approved medication in 1996 during the wave of atypical anti-psychotics brought to the market in the 1990s. It quickly developed a reputation as being an effective medication, shining in studies like Katie. Now, nothing in psychiatry really compares to Chlozapine in trim air resistance schizophrenia, which is defined as a failure of two or more adequate trials of anti-psychotics. But there is, you know, maybe some evidence suggesting that Lanzapine may be one of the more effective non-close-apine anti-psychotics, especially at supra therapeutic doses of 30 to 40 milligrams per day, as shown by studies like Ganon et al. 2023. And I do also want to talk about Zydis. I think Dr. Wang is going to talk a little bit more here. But in our original Zydis episode, we did talk about how maybe Zydis, the dissolving oral tablet, may act a little faster. I wanted to correct this. So there's actually not good evidence that it has faster pharmacokinetics or faster onset of action. So the main benefit of Zydis may be the adherence or the dissolving aspect of it, making it easier to take. The study we cited there about it maybe having earlier levels, it was pretty marginal. And really there's not strong evidence for faster onset of action. So speaking of Zydis, Zyprexa or Lanzapine is pretty useful as in impatient for a lot of reasons. So for one, it comes in a lot of formulation. So we got the regular oral, the dissolvable Zydis, as well as short acting and schermuscular. And it's nice because it works relatively quickly. It's easy to titrate for a few reasons. So number one, fairly low rates of extra pyramidal symptoms or EPS. It's not that strong of a D2 blocker. And additionally, it has built-in anti-colonersic properties. So you don't need to necessarily give a lot of Benstrapine or Diffin hydramine. Also, unlike its cousin's clasapine and Quatyapine, it's not that potent as an alpha-1 antagonist. So the risk for orthostasis and falls is not as bad as some of the other peen. So another reason why I can titrate a little bit quicker. As a strong histamine one blocker, it's pretty sedating, which is sometimes you don't want patients to be too drowsy during the day. But it can also be useful for manic patients who haven't been sleeping much as well as in cases of agitation. But at the same time, there are definitely downsides. So the biggest one is probably weight gain, metabolic dysfunction, as it tends to be one of the worst offenders among all psychiatric medications in this aspect. A lot of patients gain lots and lots of weight. And while it's strong anti-colonersic properties are good for mitigating EPS, this can cause some constipation, urinary tension, and these factors, along with the lack of a practical long-acting injectable until now, I guess, was somewhat limiting its use in long-term treatment. Just while we're talking about the weight gain quick mention, it does fall under one of those high-risk anti-psychotics that the schizophrenia bulletin paper did recommend just automatically co-prescribing that form and with franisecotic induced weight gain prevention. Yeah, and I'll jump into as well, you know, the pharmaceutical industry has been ahead of the curve on that as well with the Olanzepine and Semidorfin combination known as Leibolfi. And I can't remember, did we do an episode on that, Dr. Wang? We didn't do a separate episode on Leibolfi, but we mentioned it briefly in our general Olanzepine episode, gotcha. So, in summary, Olanzepine has been around for a while now in different different forms, formulations, products, etc. But some of our listeners, in particular, are medical students, new interns might say, "Hey, we already have an Olanzepine long-acting injectable." It's called RELPREV, was released in 2009, so what are we doing here? But before we get into that, we should look at where did the long-acting injectables first originate? Well, the first FDA-approved long-acting injectable was a formulation of flufanazine, that's brand-name prolixin, which came out in 1966, followed by Halopyridol, deconate 20 years later in 1986. Now, these LAIs are still used today with some regularity, and are much less expensive than some of the newer alternatives, although problems like higher rates of EPS, especially Tarte of Diskinesia, and the necessity of oral overlap, and potentially more pain with the sesame oil formulation, certain injection, somewhat limits their use. All right, so the first A-typical LAI was resparidone, that was specifically resparidol consta, released in 2003, and there's been multiple newer formulation sets, which include perseris and uzetti. The metabolite of resparidone, Halopyridone, also known as invega, came out with its own long-acting injection series, which includes sestena, trinza, and even a six-month formulation known as haphiara. And then there is also arapyprosyl, or bilify, the partial d2 agonist, with maintaina, aristata, and asintafi. The advantages of these newer agents was lower rates of EPS, longer lasting injections, with some not requiring overlap with an oral medication, although they do tend to still be more expensive. However, there are some free programs within hospitals that allow for a number of free injections per year, like one of the ones that I worked at, allowed you to have two injections per year covered. Anyway, this is a brief overview of LAI's, and if you want more detail, I would recommend looking up the specific anti-psychotic for each one in our podcast library, and you'll see that we dedicate a specific part of each episode to the LAI. As a quick aside, you know, LAI's a really important part of my job, because adherence is a major reason why many patients decomposate and return to the inpatient setting over and over again. Sometimes this simple matter of forgetting, but sometimes it's not like in the side effects or lack of insight, but if you look at some studies like Valenstein et al 2006, the adherence rates for anti-psychotics are not great. And other studies like Kishimoto et al 2021 find that LAI's our associates. with lower risk of hospitalization, compared with oral antipsychotics, and some studies even like tapaliate al from Sweden, suggest that LEIs were associated with a 33% lower rate of all cause mortality, including death by suicide, accident, overdose, violence. - Yeah, and like Dr. Hewitt mentioned, relprev does currently exist and has existed. And despite good efficacy data, it's almost never used. Why? Well, the answer is something called post injection, delirium sedation syndrome, or PDSS. Now, normally when something is injected like relprev, it's injected into the muscle and released slowly into the bloodstream over time. However, in rare cases, something like 0.07% of all injections, instead of gradual release, the oland's pain is instead released all at once into the bloodstream, essentially causing an oland's pain overdose. So you can see why that would be a pretty big problem. While this 0.07% number seems low, this is for each injection. And that's about 1 in every 1400 injections. So with the cumulative risk, about 1.4% of patients may be affected. There's been reports of even death as an effect of that, so it's certainly not something to be taken lightly. As a result, relprev has a risk evaluation and mitigation strategy or REMS program associated with it. So it is only dispensed at specific certified facilities and patients must be observed for three hours after each injection and also cannot drive home on the day of injection. So a lot of logistical barriers. - And I will say in my entire career, which admittedly has not been that long, I've only seen a single patient on relprev due to some of the risks, as well as logistical difficulties. And so we've kind of been waiting a pretty long time for a new long-acting formulation of oland's pain that doesn't have this risk of PDSS, and 17 years later, we may have one. Let's get into what Trusa, so this is known as literature as TV44749. And this is very important because if you do want to do a literature search, well Trusa will not show much of anything. This is kind of a recent brand name. You have to use TV44749, or another way you can look for it, type in Solaris, that's S-O-L-A-R-I-S to look for some of the studies. Now, disclaimer, as of October, 2026, today's the 20th, this is when we're recording, the full phase through results of Solaris have not yet appeared in peer-reviewed literature. So a lot of it's still in summary form. So we can't look really closely at, for example, discussion, methods. You may have to edit this episode in the future, but at the same time, we wanted to give you this information quickly. So we'll go over what's available, which includes some of the information graphs, data tables from some of the drug wraps I've seen. You can see it online as well, and we'll try to do our best. - Yeah, I'm trying to see if Solaris has any sort of meaning as an acronym, like they like to do for these studies, and I can't find one at least right now. So if anybody knows, also send us a message. - I'm curious. - All right, well, let's get into some of the details that we are wondering. So how do we deal with PDSS? Big concern, like Dr. Miller mentioned. Not a great thing to be even counseling on as part of an informed consent. Sounds scary, looks scary. It is scary. And the makers of all Drusa did decide to do a few things. So they did make the injection subcutaneous and used a type of technology known as Medincell's steady tech copolymer technology. So from what we were able to read, that upon contact with human plasma copolymers, which contain the medication, precipitate and form a solid matrix, which then entraps the alanzapine, limiting the risk of PDSS, since that risk of spread is limited. Now, the big key is so far, there have been no cases of PDSS in the clinical trials, which consisted of over 3,000 injections. Yet there is still a warning on the label, largely because of RELPREF. So despite this, no REMS program actually exists for this new LAI, we'll choose a. And so no post injection monitoring or REMS certification to date would be necessary, which may clear that logistical barrier that we're talking about here with waiting, no driving, staying there for three hours. That's quite a tough sell when you're trying to talk about a long acting injection. - So my background is in chemistry at all. So I'm not gonna pretend to know what copolymer technology is or the solid matrix thing. So let's go into more of the specific doses in kinetics, something we're a little bit more familiar with. Well, Truza is a monthly formulation and comes in three doses, 318 milligrams, 425 milligrams and 531 milligrams. Essentially, these three doses are thought to be roughly equivalent to 10, 15, and 20 milligrams of oral lance pain respectively. There is no loading dose required and no overlap necessary with oral medication, which is quite convenient. Looking at the Solaris data upon which well Truza received its FDA approval, this was a multinational multi-center, randomized double-blind placebo controlled Phase III trial in patients aged 18 to 64 years with schizophrenia. There was an initial eight-week period that consisted of 675 patients randomized to three different lance pain doses. Again, that was 318, 425 and 531 milligrams as well as a placebo group. The primary endpoint was the change in baseline pans total score at week eight. The data here shows an absolute change of negative 21.91, negative 23.44, and negative 21.93 points on pans from the three doses with differences of 9.75, 11.27, and 9.76 points compared to the placebo. And that is considered significant in the study. In doing the math, these translate to two Cohen's de-effect sizes of 0.54, 0.64 and 0.55 for the 318 milligram, 425 milligram, and 531 milligram, which respectively is 10, 15, and 20 milligram equivalents of oral lance pain. So the question is, if we're thinking of a dose response, why do we have a higher potential Cohen's de here with the 15 milligram dose equivalent and not the 20? So this is actually a really big question. I was actually curious, what are your thoughts on this, Dr. Wayne? - Well, this is actually the main question I had for the drug reps when they came to visit, but they weren't really able to give me an answer. I left my email, they said they would have their MSL get back to me, but I still haven't heard back yet. I guess, I wonder if it's just a statistical noise, something with maybe how it's administered or something just completely different. I would say that some studies show that results like this aren't entirely unusual. So obviously this is not schizophrenia, this is depression, but I know with curipersine vralar for augmentation and depression, there are some studies that show the lower 1.5 milligram dose separated from placebo, while the higher 3 milligram dose did not. But at least in this case, all of the treatment groups separated from placebo, even though the 15 milligram equivalent, what is that, the 425 seemed to be a little bit, had a little bit bigger change in pan score. - I'll also kind of redirect us and criticize this line of thinking. I don't believe there was a statistically significant difference between these values. So the conclusion here that this difference is even meaningful isn't crowded in stats. So I think we would need to be mindful of that too. I also wanna mention that following the eight-week period, there was a second phase of the study which consisted of 48 weeks as an open label extension and this is where the placebo patients were randomized across three different alansapine doses and overall discontinuation during this period was quite rare with only 5% of alansapine patients stopping compared to 4% of placebo patients. Now unexpectedly, all three treatment groups had a much higher proportion of participants experiencing weight gain even at the eight-week mark. Specifically, the placebo group had 9% of participants gain weight while the three alansapine groups had 30%, 39% and 34% of participants gain weight respectively. Now about half of the participants attained stabilization and about 20% retained remission. And once again, of the over 3,000 injections that were given, no cases of PDSS were reported or observed. - All right, so I think as we're getting to the end of the episode here, I wanna pose the question how significant as well truths are going to be in the psychiatry world. So obviously now we're getting into the opinion section a bit more. We don't have a crystal ball and this is gonna be pretty hard to predict. It's an entirely new medication. I think among the long-acting injectables, it has a pretty unique niche. Currently, excluding relprev, which was almost never used. There are technically five different antipsychotics with long-acting injectables, and that's haloparital flufennazine, resparidone, paloparidone, and erypiprosol. And, you know, dynamically, some of these are pretty similar. For example, haloparital flufennazine are both first-generation strong D2 blockers. And the kinetics might be different between the antipsychotics here with the LAIs, but they're quite similar in terms of the pharmacodynamics. Risparidone and paloparidone are even more similar, especially because paloparidone is the active metabolite of resparidone. And, you know, these are also pretty strong binding affinity medications with strong D2 blockade and high five HT2A binding affinity. So, you know, resparidone is sometimes even called the most typical of the atypicals. So, you know, in addition, I think that we're often funneled just into these antipsychotics because, I mean, my experience working in residency is that a lot of times you are picking a medication on the inpatient setting with the intention of having a long-acting injection available as an option. Yeah, and there is aeropipersol as well. So, that one's a bit different, it's a partial dopamine agnus, but kind of summarizing what Brad went through, you have a haloparital flufennazine strong D2 blocking typicals. Risparidone, paloparidone, these are strong D2, five HT2A blocking A-typicals. Aeropipersol, D2 partial agnus. So, even though there's technically five antipsychotics with long-acting injectables, pharmacode dynamically, it's more like three different types with LAIs. Obviously, kinetics can be different. There's some other differences, but, you know, with the lands of pain, it's quite different pharmacodynamically compared to the other ones available now. It's more of a moderate D2 blocker. Some people say, you know, it's actions on NMDA, GAB and turnerons, D4, five HT2A, five HT2C are some of its mechanisms of actions, although it's a lot of speculation still. But whatever it is, it's kind of a new addition as the first pain antipsychotic to have a usable LAI. And this is, I'm specifying you're usable because relprag was so rarely used due to rams and PDSS. The other thing to mention is that it is quite low risk for EPS compared to the other antipsychotics with LAIs. So, the strong D2 blockers, Halopairdolf, who fenders in especially, have high risk for Tartef dyskinesia, as well as dystonia, Parkinsonism, acathesia. Aeropipersol is overall a little bit more favorable, but it is also very high risk for acathesia. And, a lands of pain is relatively low risk among antipsychotics for all of these types of EPS. Now, once again, I don't want to glaze a lands of pain too much because the downside is that it causes a lot of weight gain, metabolic, metabolic dysfunction, and has a lot of anticholinergic burden. And as my last comment, I will say, sometimes it's hard to get excited about new medications coming up because the cost is so high and insurance has a hard time covering, but with some of the new long-acting injectables, usually patients are allowed to get a few free doses from the hospital each year. And I did confirm that this will be the case with both Truza as well, at least where I work. And I heard that we may be able to get it as soon as November 2026. Right now, wholesale acquisition cost is around 3950, so $3,950 from the latest news available. So the fact that there are free doses available is definitely positive. Yeah, all good points. And again, I think just as my last point, I want to reiterate, this is very new. There's no post-marketing surveillance data. So I think the jury's a little bit out still, as far as what the long-term benefit of this is going to look like. So I definitely am eager to see what the consensus looks like in the long run. All right. Well, that wraps it up for today. In summary, we talked about the exciting development of Alancepene, well, Truza, a new long-acting injectable formulation that, unlike RELPREV, has not had any reported causes of BDSS and does not have a RAMS program. As always, feel free to contact us at psychrounds, [email protected] for questions, comments, or future episodes suggestions. Please reach out. We love hearing from you guys. If you're a fan of the podcast, please drop us a follow rating or review as this helps us reach larger audiences. We will see you next time and have a great rest of the week.