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John M. Kane, MD: Hi. I'm Dr John Kane, professor of psychiatry and molecular medicine at the Donald and Barbara Zucker School of Medicine in Hempstead, New York. Welcome to season two of Medscape's InDiscussion series on schizophrenia. Today, we're going to discuss relapse and the use of long-acting injectable (LAI) formulations. But first, let me introduce my guest, Dr Jose Rubio. He is an assistant professor of psychiatry, also at the Donald and Barbara Zucker School of Medicine, and he is a recipient of a prestigious NIH K (research career development) award focusing on the neurobiology of relapse in schizophrenia. Jose, welcome to InDiscussion.
Jose Rubio-Lorente, MD: Thank you for having me here today.
Kane: In talking about relapse, we know that it is a very common phenomenon in patients with schizophrenia. Why do patients relapse? Is it medication discontinuation or poor adherence? And what other factors might contribute to it?
Rubio-Lorente: It is indeed a very common phenomenon. About 80% of patients who have a first episode of schizophrenia are going to have at least another episode. The first reason why patients relapse is that they very often have discontinuation of treatment. That's the number one reason, not just in terms of how frequent it is but how strong of a predictor it is for relapsing. But that's not the full story. There are people who may relapse despite ongoing treatment, and we can talk about that in a few minutes. The reality is that the biggest offender is treatment discontinuation or interruptions in the continuity of exposure that end the psychotic medication.
Kane: We know that antipsychotic medications are highly efficacious in preventing relapse. And one of the seminal meta-analyses showed a number needed to treat of three in terms of comparing antipsychotic medication to placebo.
Rubio-Lorente: That is true. At this stage of the game, not many people question that antipsychotics are highly efficacious and prevent relapses. I think that antipsychotic medications are one of the most efficacious tools we have in psychiatry. That is not something people would argue. Now, there are some people who may question how long the usage of antipsychotics is necessary and for whom it is necessary. But the fact that antipsychotics are clearly superior to placebo for preventing relapses is uncontested.
Kane: Right now we don't have any evidence to suggest there's a time at which it's safe to discontinue medication. Looking at the long-term follow-up studies of patients with first-episode schizophrenia, it seems like the need continues over time. Is that your impression?
Rubio-Lorente: It's a tricky issue. I don't think we have or ever will have the absolutely clear evidence to answer that question. Long-term studies are great because they have long-term answers, but also they are biased in the sense that it's very difficult to retain patients over a long period of time. You end up with highly selective populations. So it's very complicated to make a conclusion from them. The question is not so much whether this medication should or should not be continued long term — it's more about for a given individual, what are the chances of relapse if the medication is discontinued? We don't really have a good answer to that yet. This is a research question to which we may be able to develop better answers. Clinical information may not be enough. I don't think anyone can make a good forecast for a given individual based on clinical information alone. Hopefully over time, we're going to be able to develop neural biomarkers that may inform the question a little bit better. But at this stage of the game, it's really hard to predict who's going to relapse and who's not going to relapse. We know that most patients will. We know that 80% will — we just don't know which 80%.
Kane: Right. And is it your impression that adherence improves over time, or does nonadherence increase over time? Some clinicians feel that patients will learn if they have a relapse and that medication is important. But what do the data suggest?
Rubio-Lorente: I would make the distinction between adherence and continuity of treatment, and by continuity of treatment, I refer to whether patients are actually picking up the medication from the pharmacy and engaged in treatment. That is separate from adherence. We know that many people who are engaged in treatment are not adherent, and all of us have experienced this. I'm sure our listeners are familiar with examples of doctors who fail to complete the course of antibiotics. That's very common. What I want to emphasize are the data on continuity of treatment. These are data regarding whether someone is picking up the medication from the pharmacy, for example. We have conducted a study with the Finnish population in which we compare the use of treatment over time for up to two decades. So we have a lot of patient data for a long period of time, and we can compare different periods for a given individual. What we saw is that patients usually have this strong effect, or correlation, of time since diagnosis. The longer the time since diagnosis, the lower the chances are that a patient will discontinue treatment. In the early-phase treatment discontinuation, treatment disengagement is very, very common. As patients have been sick for a longer period of time and as they have had several relapses, they tend to stay on the treatment much longer. This is something we found. So the answer to your question is that, yes, as they age, patients get more engaged in treatment.
Kane: I guess we could conclude that patients learn that medication may be important from having a relapse. But at the same time, when a patient does relapse, it can have a lot of negative consequences. So we don't want to necessarily wait for a patient to learn how important medication is. We would like to prevent as many relapses as we possibly can. That's a good segue into the use of LAI formulations. What evidence do we have that using these formulations can actually reduce the risk of relapse or hospitalization?
Rubio-Lorente: To answer the first point, I agree with you 100%. I think it is very bad to learn about the importance of medication by having a relapse. And the reason it's very bad is that it could have been avoided. Relapse may have very bad consequences for some patients. But the most important thing is that there are many patients who don't recover their functioning to the same extent as before the relapse. So sometimes it's an irreversible phenomenon. And if you need a few of those relapses to realize that you should stay on medication, it's too late because you're never going to get back to the situation in which you're going to be as responsive to the medication as you were in the first round. That's why it's super important to be proactive about it and avoid as many relapses as possible. This is a segue to the second half of your question. Yes, LAIs have many, many benefits in that regard. I still think we tend to be a little bit reactive in the use of these medications. We need to be more proactive, preventing relapses to mitigate the long-term consequences of relapse to try to reduce the extent to which patients get resistant to treatment over time. Unfortunately, that's not what the data show. The data look like the LAI medications are used more as a consequence of someone having relapsed or as a consequence of someone having demonstrated they are not adherent with the medication. And that's too late. At that point, patients have had several relapses. You want to use LAI medications before those relapses have occurred and during a time when patients are still responsive to the medication. We did this study with claims data that clearly show that in first-episode psychosis, there's an early phase. There is an underutilization of these medications in this phase — and these medications are underutilized by and large. But in the first-episode population, they are even much more underutilized than they are with the general population. That's one missed opportunity. And then whenever they are used in the early phase, we very often see that they are used after a patient had a hospitalization or treatment failed for some reason. That's too late. That's the situation you want to avoid. You want to start using these medications much earlier on. Because to me, these are prophylactic medications.
Kane: What is the evidence that LAI formulations can actually reduce the risk of relapse or hospitalization in comparison to the use of oral medications? Do we have good data to support that conclusion?
Rubio-Lorente: We do. I think the data are very compelling, some of which come from the work you've done. But there are other investigators who have also, with very different approaches, demonstrated that these LAI medications are superior to their oral counterparts. For instance, there is the meta-analysis your team conducted in which they were looking at the efficacy of LAIs vs oral forms and using three different approaches — mirror image study, randomized controlled trial, and cohort study. And using those three approaches, the result was the same. LAIs were superior. There's also a body of literature coming from real-world data from Finland and Sweden that very elegantly demonstrates with sophisticated analyses that the periods when people were using these medications were much less likely to result in psychiatric hospitalization when compared to their oral counterparts. The effect size was an improvement between 30% and 40%. So, I think that there are multiple lines of evidence that converge in indicating that these medications are superior to their oral counterparts.
Kane: I think that's very important. But one possibility is that clinicians could be confused sometimes because if you look at randomized controlled trials, they're not always supportive of the advantages of a long-acting formulation. We see randomized controlled trials that do not show a difference between LAIs and oral formulations. We see others that do. That's where the meta-analyses become particularly important and also understanding potential differences between studies. We need to look at a lot of data from a lot of different perspectives to get a handle on this.
Rubio-Lorente: I am 100% with you. To study LAIs, it's important to not restrict to randomized controlled trials because we know — not just from the LAI literature but from the schizophrenia literature in general — that those who make it to the randomized controlled trial are a highly selected population that probably reflect about 10% of the real world. There is some elegant work that comes from Scandinavia demonstrating this. It's important to look at the literature with this important consideration in mind. One example are the data on time-to-treatment discontinuation. Recently published were the data from Europe suggesting that with a randomized controlled trial design, there were no differences between the time to discontinuation of oral medications and LAIs. If you look at it from the perspective of real-world data from registries in Scandinavia, you can see a very, very important effect. You see that patients tend to stay on treatment much longer when they are on the LAI compared to their oral counterpart. This is something that's very important when looking at the literature. It's important to not make judgments based just on one approach to the data because in such a particular population and method, it requires a more multifaceted study.
Kane: Obviously we've been talking about the prevention of relapse and hospitalization. And you suggested that there are a lot of data supporting the use of LAI medicines. On the other hand, we don't want to give our listeners the impression that once a patient is on an LAI, they're never going to relapse again. I know that's been a very important focus of your work. Can you talk about that a little bit? Why do patients still relapse even when they're definitely getting the medication that's been prescribed?
Rubio-Lorente: Right. That is something we worked on. Indeed, there are patients who, despite responding to a medication with a LAI, may still experience a relapse. This is something that has been reasonably well studied. We found out that there were about 20 events per 100 patient-years. This means it's not completely unheard of. I'm sure that most clinicians may have seen it in the clinic. The reason why patients relapse despite being on the medication are not yet very well understood. We found out that there were some epidemiological predictors that increased the risk. One of them was having residual symptoms. Patients who did respond to the medication but still had some lingering residual positive symptoms were more likely to present with a relapse of their symptoms after being on the LAI. Also, experiencing tardive dyskinesia was another relatively strong predictor, which could suggest that it could have been mediated by dopamine supersensitivity. However, the data on that are complicated. So, I wouldn't jump to that conclusion. Those were some suggested mechanisms, but we still need to do a lot to understand better what's happening in the brain of these patients and why these medications that were once effective are no longer effective.
Kane: One risk factor you're suggesting is whether or not a patient has residual positive symptoms. So, if the patient is in true remission, they're less likely to relapse. And the patient who continues to have some positive symptoms, even though they might have improved, there are still positive symptoms that are residual. Those patients are at greater risk.
Rubio-Lorente: Correct. And we looked at whether it was a variation within the normal fluctuation of symptoms, and this was clear relapse that was associated with worse functioning. And it was a meaningful difference in terms of symptom severity compared to the baseline. So, yes, if there are patients who are not fully responding to their medication, chances are good that these patients are the most likely to present with a relapse over time.
Kane: This is more on the on the research end of things, but can you tell us a little bit about the work you're doing using brain imaging to try to better understand this?
Rubio-Lorente: Yes. So, instead of reinventing the wheel, what we are doing is applying some of the work that has been done on treatment response to relapse. Our institution has done a lot of work developing biomarkers of treatment response using neuroimaging. And the first question we had was that it seems there is a biomarker that reflects striatal functioning, and it seems to predict reasonably well who's going to respond to medication and who is not going to respond to medication. How does this behave when a patient relapses despite being on treatment that was guaranteed via an LAI? That is the first work we did. And we did show that the patients who relapse on LAIs had a particularly low value of this particular biomarker, which suggests that they behaved initially as those who are treatment responsive. In other words, these patients looked like people who are treatment responsive from their biomarker type, but over time, they lost that treatment response. That could suggest it was not so much issues with striatal functioning, but it might have been some extra striatal mechanisms that were involved. We have another study in which we are trying to replicate these findings, and that's underway. But hopefully we will look at whether there is something about the way the resting state connectivity operates, particularly in the striatum, which can inform us about some of what may go awry in these individuals.
Kane: That's very exciting. It's important that you've chosen a strategy, which is somewhat unusual. And many of the studies that try to identify predictors of relapse have involved patients on various medications — usually oral medications. That could lead to a confounding with nonadherence. But by studying just patients receiving LAI medications, you've eliminated that potential confounding. That's a very elegant approach. Using MRI and following patients over time, as you suggest, could be helpful in understanding what's actually going on.
Rubio-Lorente: Drug effects are a big confounder in much of the clinical neuroimaging literature. So we tried to mitigate that confounding as much as possible. I think that's going to be critical to develop these paradigms. And in the real world, things are going to be much more complicated. We are doing this research with the hopes that one day it'll be possible to use it in the clinic. We'll cross that bridge when we get there. Things in the real world are much more complicated, and adherence is not as easy to tell at a given time. Now that we are at the stage of developing these biomarkers, it's very important that we do a good job isolating what the effects are that may be confounding from the medication vs true effects that may inform about true validity of these potential biomarkers.
Kane: That's great. I guess it's possible that some patients are not suffering from a dopaminergic hyperactivity — to put it in a very sort of simplistic way of describing the illness — but that perhaps other neurotransmitters are involved. That may also relate to your finding about tardive dyskinesia being a risk factor. Perhaps patients who don't have as much of a hyperdopaminergic state may be more vulnerable to developing tardive dyskinesia. That's something we don't really know, but it raises some interesting possibilities.
Rubio-Lorente: We are entering a very interesting stage of this line of research because we have medications in the pipeline that are not directly dopaminergic. They may have some effects downstream, but that's not the initial target these medications have. So by using these medications as approaches to nondopaminergic pathology, there can be exciting studies that may emerge. I'm very excited to see what comes along with the development of these new medications.
Kane: Yes, that'll be very interesting. And we can learn whether those medicines will work when other medicines have failed or whether they'll have different effects on things like negative symptoms or cognitive dysfunction. We're looking forward to learning more about those new drugs. We've covered a lot of territory. Today, we've talked with Dr Jose Rubio about relapse and about the use of LAI medicines. We've highlighted the importance of medication and preventing relapse, the frequency of which patients have difficulty adhering to medication on a consistent basis, and the value of LAI formulations in reducing the risk of relapse and rehospitalization — even though not every single study supports that. When we look at the data in their entirety using different strategies, it does seem to be an important effect. Yet, as you mentioned, LAI formulations are underutilized, particularly early in the illness. We've also highlighted the fact that some patients, even when receiving so-called guaranteed medication, will still experience a relapse. It's much lower than the rates on oral medication, but it still can occur. And you've talked about some risk factors, including residual positive symptoms for example, and also the very exciting research you're doing in terms of trying to better understand the neurobiology of relapse. Thank you all for tuning in. If you haven't done so already, take a moment to download the Medscape app to listen and subscribe to this podcast series on schizophrenia. This is Dr John Kane for InDiscussion.
Listen to additional seasons of this podcast.
Resources
The Nature of Relapse in Schizophrenia
What Is the Risk-Benefit Ratio of Long-term Antipsychotic Treatment in People With Schizophrenia?
Long-Acting Antipsychotic Therapies for Patients With Schizophrenia
Long-term Continuity of Antipsychotic Treatment for Schizophrenia: A Nationwide Study
Antipsychotic Use Among Persons With Schizophrenia in Sweden and Finland, Trends and Differences
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Cite this: Long-Acting Injectables and Schizophrenia: Mitigating the Risk for Relapse and Rehospitalization - Medscape - Mar 22, 2023.
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