Chapter 3: Long-acting Injectables

GLOBAL NOTE: Highlighted passages represent KOL discussion sections that were built into the approved script/discussion guide.

Dr. Roger McIntyre: Welcome back to this clinical consult video series on Bipolar 1 disorder, sponsored by Otsuka Pharmaceuticals and Lundbeck. In the previous two episodes we have talked about the importance of early diagnosis and treatment of patients with BP-1, and we've also reviewed standard treatment regimens and challenges related to adherence. In this episode, we're going to explore the use of an LAI antipsychotics in the management of bipolar disorder as opposed to daily oral antipsychotics LAI formulations are administered by a healthcare professional in the clinic once every two weeks to every two months, depending on the agent used. This approach can support improved therapy adherence, consistent dosing, and regular check-ins with clinicians at time of injection. Dr. Broder, can you describe the degree to which ALI's can improve adherence among patients with bipolar disorder?

Dr. Todd Broder: Sure. I'll share results from a retrospective analysis that use data from Truven Health Analytics Market Scan Commercial and Medicaid claims databases to evaluate therapy adherence and discontinuation rates for patients with bipolar disorder who either change from one oral antipsychotic therapy to another or began a long-acting injectable antipsychotic. In the analytics sample, there were 1,672 patients with bipolar disorder who used long-acting injectable antipsychotics and 9,672 patients who used oral antipsychotics. Patients were considered non-adherent if the proportion of days covered were PDC over the first-year post. Index was less than 0.8. This was calculated by dividing the number of available days of index therapy by 365. Discontinuation was defined as either a gap of 60 or more days in available days’ supply during the entire follow-up or a switch to a non-index therapy within 60 days following index therapy discontinuation. The average follow-up period was 627.4 days for the LAI group and 639.5 days for the oral therapy group. The study finding showed that long-acting injectable users achieved a significantly higher medication adherence rate during the year post-index with 30.9% of LAI users having a 0.8 or greater PDC as opposed to 21.5% of oral users. The p-value on this was statistically significant, less than 0.001. The discontinuation rate was also significantly lower among LAI users versus oral users at 67.9% versus 77.4% respectively, p-value again less than 0.001. The median time to discontinuation was 149 days for LAI users and 99 days for oral users.

Dr. Roger McIntyre: Just to reiterate what you said, Dr. Broder, LAIs were associated with a significantly higher medication adherence rate and a significantly lower discontinuation rate than that of oral therapy with a p-value of less than 0.001.

Dr. Todd Broder: Yes, and the rate of adherence to long-acting injectables can be further supported with behavioral interventions at the time of injection as evidenced from the finding of a six-month prospective single-arm intervention trial regarding non-adherence in patients with bipolar disorder. In this particular study, patients had self-reported adherence issues defined as missing oral therapy by 20% or more in the past week or past month. At study initiation, the LAI antipsychotic aripiprazole either replaced their oral antipsychotic through a tapering regimen or supplemented their treatment if they were on a non-antipsychotic therapy. At each monthly injection, a social worker provided a psychosocial intervention based on the individual's unique barriers to adherence. This approach actually considerably improved adherence rates. From the initial screening to 24 weeks, the average proportion of missed medications in the past week significantly changed from 50.1% to 16.9% with a p-value of less than 0.001 as measured by a self-reported questionnaire. This trend was also reflected when measured over the past month with the average proportion of missed medication improving from 40.6% to 19.2%.

Dr. Roger McIntyre: Great. Thanks for sharing. Hara, earlier you said that non-adherence to bipolar treatment can contribute to future manic relapse, a higher number of hospitalizations, and a greater risk for suicide. Can you provide further insight into why adherence is so important for patients with bipolar disorder?

Hara Oyedeji: Absolutely, Dr. McIntyre. I can share results from a review of six observational mirror image studies that compared clinical outcomes from 12 months prior to LAI antipsychotic initiation to clinical outcomes 12 months post-initiation among patients with bipolar disorder. This comparison of outcomes across equal periods of time without and with LAI antipsychotic therapy is thought to be particularly appropriate for assessing LAI efficacy in treatment of BP. Overall, the researchers identified a consistent reduction in hospitalization rates when comparing the 12 months before and after LAI initiation. Outcomes from one study had shown a reduction in hospital rates during this period from 62% to 22.5%. Results from another study had shown a reduction in rehospitalization rates from 45.5% to 18.2%. The improvements demonstrated in both of these studies were statistically significant with a p-value less than 0.001. Similarly, findings from three studies showed that emergency department visits were lower for patients during the 12 months following LAI initiation. The researchers also concluded from the findings that LAI treatment was associated with a lower number of mood relapses overall. And tying into what we discussed earlier, reducing relapses helps to preserve cognitive and functional abilities, reduce likelihood of disability, and support patients in maintaining their work and their daily activities. So it's a very important goal in the management of bipolar 1 disorder. The improvements identified in this review were thought to be due to the better treatment adherence associated with the use of an LAI antipsychotic.

Dr. Roger McIntyre: We've also discussed the importance of early diagnosis and treatment initiation for patients with bipolar disorder, Hara. How early in the treatment course can an LAI be initiated to support adherence and improve outcomes?

Hara Oyedeji: Great question. Well, currently, there is a paucity of official recommendations regarding when to initiate an LAI for treatment of bipolar disorder and an overall lack of consensus across treatment guidelines. However, some experts believe that the second manic or depressive episode is the point at which bipolar disorder is confirmed to be recurrent, and maintenance therapy with an LAI is warranted. For certain patients at high risk of recurrence, it may be appropriate to initiate an LAI as early as the first manic or depressive episode. As I said earlier in the program, preventing manic episode relapse up front is imperative to supporting positive outcomes. Initiating an LAI early can help address issues with nonadherence and help prevent the future manic episodes. Before initiating an LAI, experts agreed that efficacy and tolerability of a specific therapy should first be established with its oral formulation. According to results from a survey of 34 expert researchers and LAI prescribers, oral therapy may be initiated for a short duration of 4 to 14 days to monitor for patient response before LAI initiation.

Dr. Roger McIntyre: Thank you, Hera. As you said, initiating an LAI early in the course of treatment can be an important strategy for reducing risk of manic relapse and improving outcome. Let's pivot now to review LAIs for BP1. We're going to focus our discussion on two LAIs that are currently approved by the FDA as maintenance model therapy for BP1, which are aripiprazole, dosed at 960 mg once every two months, and risperidone, dosed at 25 to 50 mg once every two weeks. Dr. Broder, can you share the key efficacy data associated with aripiprazole for BP1 maintenance treatment?

Dr. Todd Broder: Certainly. The efficacy and safety of aripiprazole, 960 mg, which is a once every two-month injection, was actually established based on trial results from its predecessor, once monthly, 400 mg dosing option. In the 52-week randomized trial, 266 patients with BP1 disorder were equally randomized to receive either aripiprazole, 400 mg, long-acting injectable, or placebo after completing a two-phase oral aripiprazole stabilization period. Of those participants, 48.1% in the aripiprazole 400 LAI group and 28.6% in the placebo group completed the study. Results showed that aripiprazole, long-acting injectable, was associated with a significant delay to any mood episode compared to placebo, with a p-value of less than 0.0001. Risk of any mood episode recurrence over a 52-week period of time was reduced by approximately 50% with the aripiprazole LAI compared to placebo. Analysis by type of mood recurrence demonstrated a statistically significant longer time to recurrence for both manic and mixed episodes, but no difference in delaying time to depressive mood episodes. Notably, the median time to therapy discontinuation for any reason was significantly longer with aripiprazole LAI at 345 days than placebo at 170 days, with a p-value equal to 0.0026. Ultimately, the authors concluded that the efficacy outcomes were similar to that of oral aripiprazole monotherapy for maintenance of BP1. Similarly, a 32-week open-label trial that evaluated the safety, tolerability, and pharmacokinetics of aripiprazole 960-mg LAI compared to aripiprazole once-monthly 400 mg LAI. Outcomes showed that aripiprazole 960 mg LAI showed similar efficacy to aripiprazole once-monthly 400 mg LAI. A 12-month mirror image study was also conducted to explore rates of hospitalization among Japanese patients with BP1 who initiated aripiprazole once-monthly. The results demonstrated that rehospitalization rates between pre- and post-initiation of aripiprazole LAI significantly decreased from 59% to 18%, with a p-value of 0.001. And total hospitalization days also significantly decreased from 34.9 days down to 14.4 days, with a p-value equal to 0.008.

Dr. Roger McIntyre: Thank you for that overview, Dr. Brody. Hara, please share with us, if you could, the risperidone efficacy data.

Hara Oyedeji: Of course. Risperidone LAI efficacy compared to placebo was explored among patients with BP1 experiencing current or recent manic or mixed episodes. Following an oral risperidone stabilization period, 303 patients were randomized one-to-one to receive placebo injections or risperidone 25 mg LAI every two weeks for up to 24 months. The median duration of exposure to intervention was 280.5 days with risperidone LAI and 151 days with placebo. Results demonstrated that the time to recurrence of any mood episode was significantly longer with the risperidone LAI than placebo, with a p-value of less than 0.001. This difference was significant for elevated mood episodes with p-value of less than 0.001, but not for depressive episodes. In the randomized phase, 30% of patients receiving risperidone LAI experienced a recurrence versus 56% of patients receiving placebo. The likelihood of recurrence in the risperidone LAI group was less than half than that of the placebo group. Results from a one-year retrospective cohort study demonstrated that the one year following risperidone LAI initiation compared to the period before therapy initiation was associated with significantly lower re-hospitalization rates for any mood episode overall, P value less than 0.0001. And for manic episodes, P value less than 0.0001. And depressive episodes, P value equal to 0.0002 individually.

Dr. Roger McIntyre: Hara, what is the general safety and tolerability of aripiprazole?

Hara Oyedeji: Weight gain, insomnia, and nasopharyngitis are some of the most common side effects associated with aripiprazole or risperidone LAI to treat BP1. Use of the aripiprazole LAI has also been commonly associated with akathisia, whereas the risperidone LAI has been commonly associated with headache and depression. Based on the information and clinical insights shared today, clinicians may consider these agents earlier in the course of management for patients with BP1.

Dr. Roger McIntyre: As we have discussed, the LAI formulations for both aripiprazole and risperidone have demonstrated efficacy and safety as monotherapy treatment for BP1. They may offer an important treatment option for patients with BP1 who are prone to nonadherence and or manic relapse. OK, let's take another pause so we can share some clinical perspective from practice with the use of LAIs.

This is a question to both of you now. Can you describe your use of LAI antipsychotics for patients with bipolar disorder in clinical practice?

Dr. Todd Broder: Yes, and I'm sure Howard and I have different perspectives based on our clinic settings here. As an inpatient psychiatrist, again, I have been on somewhat of a mission to initiate long-acting injectables earlier on in the disease state for schizophrenia for many years. Over the last several years, I have been utilizing long-acting injectables much earlier on for the use of bipolar disorder as well, particularly since two-month injectables have been available. That really has added a convenience for my patients. But, for me, using long-acting injectables in an inpatient setting, when patients are often coming in in the wake of a manic episode and as they're showing improvement, they're looking at some of the destruction that episode had. When I simply talk to them about their options and say, hey, I've got an option for an injectable medication that you've actually been on in the past in an oral form, same medication, different mode of administration that's been proven to reduce manic episodes by X percent or proven to delay hospitalizations, I think patients are in a unique position at that time where they're very ready to accept something that could have a major impact on the outcome of their disease state and their life overall.

Hara Oyedeji: So, in the outpatient setting, it may definitely be a little bit different because we may be seeing patients at a different point in their disease trajectory. However, I firmly believe it's never too late. And so offering it once again at the very first opportunity, even if that's later on in their disease journey, is something that generally I would do. And so using LAIs is an approach that we rely on in the outpatient setting, at least where I work at. And I definitely encourage other practitioners working in outpatient to make sure that that is something that they're considering in their toolkits as well. So at any point in time, we want to definitely offer that.

Dr. Roger McIntyre: Thanks to both of you. Our next question is, at what point in the disorder do you typically aim to initiate LAI to treat bipolar disorder? I may just preempt by saying, for me, it's anywhere in the illness journey for any patient. So, may, open to both of you. Where do you consider it with respect to initiating the LAI?

Dr. Todd Broder: I agree at any point in the patient journey, but we just looked at data on two long-acting injectables with regard to the outcomes in bipolar 1 disorder. And the data really is quite profound to the point that I think back to this discussion of informed consent. Treating any patient with bipolar 1 disorder and not discussing with them, at least, the potential benefits of a long-acting injectable, I think we're missing the mark there, really. And with regard to a truly obtaining informed consent, which we all write in our notes right at the end of our discussion, informed consent obtained, what does that really mean? With regard to long-acting injectables, when you have this type of data, we really do owe it to our patients. We have somewhat of a duty to our patients to let them know the potential benefits of this treatment option. So, for me, if I feel confident that this is a true blue diagnosis of bipolar disorder type 1, I'm discussing a long-acting injectable right at the onset, even if that's a first episode.

Hara Oyedeji: And one of the things that I want to add to Dr. Broder's point is this piece of collaboration. Even though we're in different settings, I might work outpatient, Dr. Broder inpatient, it's really important that we're still collaborating. At some point in the care and in the journey of the patient, if they have the experience of having to come out of a hospital admission, they're in the care of outpatient providers. And so, it's really important that we want to continue with whatever it is that they have been discharged on. But if a long-acting injection was not done on the inpatient unit, oftentimes, that's a conversation that we're having. But with this collaboration point, I've had a great opportunity to work with other providers that are treating these patients. And we've been able to agree, listen, maybe this is something that needs to be initiated while they're actually with you on the unit. But as to your point, Dr. McIntyre, at any point in time during the patient's treatment, we want to be able to offer long-acting injections as an option.

Dr. Roger McIntyre: I love your point about the collaboration. And in addition to having a pragmatic part to that, there's also education part to that I've often found that amongst my colleagues who work in allied specialties that we depend on often have different understandings of LEIs than other groups do. And I think it's an area where there has been maybe a knowledge gap, and in some cases, even misinformation about what LEIs can do and what their indications are and so on and so forth. To keep going with this topic about knowledge, during initial patient counseling, how might you educate someone who's being hesitant to initiate an LEI? And what are the common reasons for hesitation?

Dr. Todd Broder: So I deal with this on a daily basis on an inpatient unit. And I feel very strongly about this. I actually blame us, the clinicians, mostly for the climate of what we deal with, with regard to resistance for an injectable. And I think that's because we have, for many years, created an environment where injection equals punishment on inpatient units, right? Patients come in and we say, oh, if you're acting up, you're going to get a shot. If you are not taking your medications, you're going to get a shot. And we've coupled this concept of injection, bad, punishment. And it actually was, interestingly, this came to my attention. I was over at my dad's house. He's older and he's suffering with emphysema and type 2 diabetes. And he's an old school guy from Philly, hates going to the doctor. And I was over his house, and he was getting ready to go to the doctor and he seemed to be in somewhat of a good mood. And I said to him, what's going on? You seem a little upbeat today. He said, "Oh, I'm going to the doctor." And I said, "What are you happy about? You hate that guy. You're always talking smack about him." And he said, "Well, I'm going to get my B12 injection today." And I said, "Oh, what's good about that?" He says, "Yeah, I feel better after I get my B12 injection." And it dawned on me that universally, we don't hate injections. There's all sorts of injections that people are willing to accept, B12, testosterone injections and so forth. And I really started to apply this mentality on the inpatient unit and explain to patients, hey, this is not the injection that you might've got when you were agitated or manic or psychotic, where you were laying in bed, sleeping and drooling. This is a sustained release of a medication that you may have already been on, same molecule in many examples. So just letting patients know the difference between a short acting injection and a long acting injectable and what that means in terms of how they're going to feel and the potential benefits they may experience from that.

Hara Oyedeji: So it's very interesting. I got my background started in nursing in trauma emergency psych, and I'm so proud of that. Working in Baltimore, where my practice is, I've really been able to work with some patients that have really shared and taught me a lot. And as a nurse at heart, education is really where our strength lies. And I've learned that a lot of our patients are suffering with trauma. And as clinicians, it's important that we understand the concept of trauma-informed care, as well as understanding the concept of recovery model in psychiatry and mental health, and really putting the patient at the helm. I mentioned earlier that sometimes it may not be on the very first try or when you're having that first [INAUDIBLE] offering an LEI that you'll get the patient to have buy-in, but over time, building that trust and providing the education and really getting to the crux of what is it about an injection that is a barrier for you. And for many of my patients, it's not necessarily the needle. I'll have conversations about tattoos, for example, which I absolutely love them and have them. And I'll say, listen, I know that that beautiful piece of art that you're wearing probably took an immense amount of time and a lot of needle, a lot of time under a needle. So what is it about the injection? And when we really get down to it, there are other things in our patients' lives that might be an issue with regards to the trauma. And so I always encourage a collaborative and an interdisciplinary team approach, right? Because having the family involved or having others who can also assist in that education process is a really big key. But eventually over time, when you really break down those barriers, you're able to kind of get a better understanding and a feel for the patient of where they are and where they are in accepting a long-acting injection. And I've had many great situations where patients have said, you know what, I'll give this a try. And eventually, it is something that overall has worked out for a lot of my patients with regards to opting for that LAI versus an oral treatment.

Dr. Todd Broder: Such a good point. You talk about trust, which can be a challenge on an inpatient unit. For the most part, I'm not the doctor that is typically treating these patients in an outpatient setting, and they don't know me, and now I'm asking them to trust me with a new option. So trust is a big, big part of this game, I think.

Dr. Roger McIntyre: Well put. Many moments, we had just a couple more discussion points here. So we've got a few minutes left. How do you educate patients who feel as though they are doing better and that they think they no longer need an LAI?

Dr. Todd Broder: That is always I think, the hardest bump in the road. Because it's the reason most of us stop our medications. I mean, how many times do we get a prescription for an antibiotic and say, I'll take this for 10 days, and in five days, I feel great. I just stopped. I think that's human nature, and I think it's just a frequent reminder of maybe, just maybe, part of why you're doing so well is because you're on a long-acting injectable, because you have constant, stable administration of medication available. And again, going back to some of the social issues, many times I will say, isn't it nice that mom or family are no longer questioning you about taking your medications, that nobody questions whether you're on it or not? We've just sort of eliminated that conflict altogether. So I try to point out the potential benefits there.

Hara Oyedeji: Agreed. I think this is something that is, for many of us as clinicians, we deal with this question often. Well, why is it that you stopped taking your medication? Well, I was feeling better. And so having this discussion, then come back around to, well, why do you think you were feeling better? I think we have to balance out this concept of risk versus benefit, and I usually present it to my patients that way. Listen, there's a risk and a benefit to medications. Either way, you cut it, right? But there's also a risk to not taking medications that we know have kept you stable, and if you come off of them, what that could really look like. And so, I try to empower my patients to say, listen, really look at this from an objective point of view, and really consider what that looks like and weigh the consequences. Nothing is perfect. I've had patients that have decided to say, yes, I want to come off of it, and some of those same patients who have later on actually come back and said, I want to get back on my injection because I know I'm not going to take my oral medication, or unfortunately have decompensated because in not taking the injection, not taking the oral medication, the symptoms just tend to rebound and come back. And so I think it's a constant educational conversation that you have to have, but that's why we want to make sure we're having those touch points with our patients, and really, I emphasize this with my students as well, just because one is on a long-acting injection doesn't mean that you're not seeing the patient as often. We want to make sure that we're still seeing them and monitoring and keeping in touch to maintain that trust and also keep them as healthy as possible.

Dr. Roger McIntyre: So when given the choice between a shorter and longer-acting LAI, which do patients typically prefer and why?

Dr. Todd Broder: I think there are a number of approaches to take to this question. There are a lot of moving parts to it. For me, on an inpatient unit in St. Augustine, a very touristy area, I often will have patients down here on vacation and they forget their medications, or maybe they're staying up too late or drinking alcohol, or for whatever reason, they have an episode while they're on vacation and end up on the inpatient unit. And now I have to initiate medication and then bridge the gap to get them home. And I may not be able to get an appointment for them within three or four weeks. And they may be still in Florida for another couple of weeks. So for me, a longer lasting LAI on initiation in an inpatient unit can buy me time for bridging the gap between inpatient and outpatient. I was talking to a nurse practitioner, a friend of mine at Community Mental Health here, about that concept two-month versus one-month long-acting injectables. And I use them both. And she said to me, well, I find it beneficial to see my patients monthly. So I prefer to use a one-month injection. And I said to her, oh, so when you have a patient on an oral medication, do you see that patient every day? And I was sort of being snooty a little bit with my response. But my point was, is the administration of the medication is not necessarily defining the touch point that we have for that patient. You certainly can still see your patient on a monthly basis, even though they're receiving an injection every two months.

Hara Oyedeji: And to Dr. Broder's point, I agree completely, right? It does not determine the touch points, so to speak, when you're seeing your patient with regards to how long that injection is. But I also appreciate the fact that we can have options as clinicians, because I think you have to tailor the situation also based on the needs of the patient and what they're dealing with. So in our practice, we have a hybrid model. We implement both inpatient, in-person appointments, but we also have a nurse that does go out, for example, to give those injections. And we also have patients that opt to come and see their provider by telehealth. And so that has opened up a wide array. I think initially when telehealth really started coming into play, especially during the pandemic, there were questions about how are we going to continue our patients with injections? And so obviously, as we see telehealth is here and has opened up avenues for many patient populations, we've been able to figure out ways to continue on with offering those long-acting injections while still maintaining those appointments with our patients. But having the option as a clinician for a one-month may really work in some situations depending on what the needs are. But a lot of times patients actually really enjoy having that flexibility of a two-month option, especially during different times of the year with seasonal changes, there's also vacations. And so having the opportunity to have a longer period of time where they're not having to come or having to get an injection really opens things up and has been a benefit. At the same time, a one-month option is also great for those patients who like a little bit more consistency or have more of a regimented schedule or routine that they stick to.

Dr. Todd Broder: Yes. And I live in an area where there are some rural surroundings. Some of my patients will have to travel quite some distance and they may not have a car. They may have to secure a family member to get them to the clinic and having a two-month injection is a really nice option for them because they could potentially touch base telehealth in between. But one of the things that I've really loved about a two-month injection, which I hadn't even considered in the beginning, is I think as an inpatient psychiatrist, how often we switch doctors, right? I do a seven on seven off work week and the new doctor comes in and maybe that's me. And there's this concept of projective identification with the patient. I want to feel effective. I want to come in and make a change or do something. And I say, oh, this patient's not responding as well as I'd like, I'm going to change their medication. And maybe they've only been on that medication a few days or a week. And when you look at the data for schizophrenia or bipolar disorder, how long do we expect it to take for a new medication to really work? And sometimes the answer to that is somewhere between four and eight weeks. And one of the things I've really enjoyed about a two-month injection is I get the opportunity to rule in or rule out that medication in that first administration. I look at that over an eight-week period and say, OK, did we get the results that really wanted and know that it was not due to poor adherence. So it gives me some clarity about that particular medication.

Dr. Roger McIntyre: Really nice pearls and really wonderful insights. Our final formal question is, again, this is the crystal ball, I guess. What role do you anticipate LAIs will play in bipolar disorder management in the future?

Hara Oyedeji: I definitely think LAIs have really made their mark. And as we continue to move forward, year after year, it's amazing to hear more providers, more practitioners who are utilizing LAIs when and if the time calls for it and if the patients prefer for it. I really think that it's going to cement itself with regards to bipolar disorder as a best practice. We already know that in the treatment of schizophrenia, long-acting injections really, if the patient prefers, are best practice. And it will be amazing to see LAIs cement themselves in the same way when we start looking at our clinical practice guidelines.

Dr. Todd Broder: Sadly, I think it's going to take ongoing education for our providers. I look at the uptick of long-acting injectable use for schizophrenia in our country compared to Europe. And sadly, we are really falling way behind still. And the truth is, it's the patients who suffer from that. So I think it's going to take quite a bit more education to move the needle where it ought to be, which I do think that would include using not only more long-acting injectables but offering them much earlier in the disease state. I think we're allowing patients to lose too much before we step in with long-acting injectables.

Dr. Roger McIntyre: Well, points well taken. I've had the incredible privilege of being able to meet colleagues and visit hospitals in different parts of the world. And Dr. Broder, your comment's well taken. I've seen that firsthand, how the utilization of the LAIs in bipolar disorder, as well as schizophrenia, are higher in some parts of the world, indicating to me this extrinsic factors that need to be modified through education. And I think above all else, again, making this treatment option known to the person with lived experience, so they can make an informed decision as part of shared decisions with their healthcare provider. I think is our job number one, frankly, to get that option on the table as part of a sort of around the horn, so to speak, conversation of all the treatment options we have. So thank you robustly, both of you, for your insights. As we wrap up this video in series, let's recap some of the key takeaways. As we discussed, bipolar disorder typically presents with chronic and debilitating symptoms associated with mood instability, particularly those that occur during the manic episodes associated with BP1. LAI antipsychotics offer an important therapeutic option for delaying time to relapse of manic episodes in BP1. They help to increase adherence rates, reduce discontinuation rates, and improve clinical outcomes such as reduced hospitalizations. In addition, they may be initiated early in the disease course to preemptively reduce risk of recurrence and the harmful consequences of repeat occurrence. With regular injection appointments, clinicians are better able to connect with their patients and provide consistent educational and behavioral support along the patient journey.

With that, thank you, Hara and Dr. Broder, for participating in this important discussion today, and thank you all, all of you, for joining us for today's program.

Dr. Todd Broder: Thank you, Dr. McIntyre.

Hara Oyedeji: Thank you so much, Dr. McIntyre.