Schizophrenia Podcast

Relapse in Schizophrenia: Why It Occurs, How Often It Occurs, and What We Can Do About It

John M. Kane, MD; Jose Rubio-Lorente, MD


December 07, 2022

This transcript has been edited for clarity.

John Kane, MD: I am Dr John Kane. I am a professor of psychiatry at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. Welcome to Medscape’s InDiscussion series on schizophrenia. Today we’ll be discussing relapse in schizophrenia. How often does it occur? Why does it occur? And what can we do about it? First, let me introduce my guest, Dr Jose Rubio, who is an assistant professor of psychiatry at the Zucker School of Medicine at Hofstra/Northwell. Jose’s work focuses on understanding the mechanisms of relapse in schizophrenia, as well as developing risk biomarkers. For this, he works with epidemiologic as well as neuroimaging data sets, paying special attention to the relationship between adherence with maintenance treatment and relapse. And his work is supported by the National Institute of Mental Health. Jose, welcome to InDiscussion.

Jose Rubio-Lorente, MD: Thank you very much, John.

Kane: Schizophrenia is often described as a chronic and relapsing illness. We know that some patients may not be vulnerable to relapse, but we have a hard time identifying who they are. There’s been a lot of discussion lately about possibly discontinuing medication in some patients, but for most patients, the risk for relapse is pretty high. Can you tell us, first of all, why is relapse so important? And then tell us a little bit about how common it is.

Rubio-Lorente: Relapse is a very difficult situation that most people with schizophrenia, unfortunately, are going to be exposed to. The reason why it’s so important to prevent is that it can have dire consequences. First, it can undo the progress that people have made toward recovery. We often see people who have a first psychotic episode, or even a second or third, who are trying to get back on their feet. They’re trying to reconnect socially with their peers. They are trying to get a job and maybe go back to school. But if they have a relapse, all that work is undone, and it is very difficult to go back to school or reconnect a second time or even a third time. It’s a very large threat to their ability to recover.

One aspect I find most concerning about why it is an outcome we must prevent is the fact that most people are going to not respond as well to the second or the following time they get treatment, as opposed to the time before the relapse. We know this from a couple of studies that have looked at this differently. And I think that the evidence is quite compelling that most people don’t get back to the level they were before they had the relapse. If we are able to prevent relapses and not just facilitate recovery, hopefully we will prevent people developing a lower ability to improve on antipsychotic medication once they are put back on it. So certainly, it’s something that I think should be a target of treatment and prevented as much as possible.

Kane: When we talk about relapse, we’re mainly talking about the recurrence of positive symptoms, right? The delusions, hallucinations, and things like that. It’s not so much the negative symptoms, which some patients may experience on an ongoing basis. The relapse is more of a recurrence of some of the original symptoms that may have led to the person being hospitalized in the first place.

Rubio-Lorente: Absolutely. Unfortunately, we still do not have good treatments for negative or cognitive symptoms of schizophrenia. And one of the conditions that’s inherent in the definition of relapse is that the person must have responded to treatment first. The assumption is that they got some benefit from an intervention and the benefit is gone for some reason — it was never there, or it was a very mild response for negative and cognitive symptoms. So that’s why, unfortunately, the concept of relapse does not apply as much to those symptom domains compared with positive symptoms.

Kane: Let’s talk for a minute about the risk for relapse. Some patients want to discontinue medicine because they don’t like the idea of taking medicine. And they feel better, as you said, if they respond well to medicine. So if someone doesn’t take medicine, what’s the risk for relapse, and what’s the risk for relapse if they do take medicine?

Rubio-Lorente: These are very important points. We know from studies that have been conducted over the past 20 or 30 years that most people with schizophrenia are going to have relapse. In fact, they’re going to have relapse multiple times. There are some data suggesting that it’s probably over 80% of people who have a first episode who will have a second episode. Unfortunately, it is very common.

Nonadherence with antipsychotic maintenance medication is the number one risk factor in terms of how common and impactful realpse is in schizophrenia. Typically, when someone has acute psychosis, we provide treatment. Among other things, we use antipsychotic medicines. And typically, we continue these medicines after their symptoms are better. The reason we continue them is not that we expect their symptoms are going to decrease any further but to prevent the symptoms from coming back in the future. That’s what’s called the relapse prevention phase of treatment.

Unfortunately, most people are going to stop the drugs at some point. We have looked at this in various ways, but we know that virtually everybody is going to at least have an interruption of treatment. Most people are going to have many interruptions of treatment. And when that happens, the risk for relapse goes up by 400%. So, it’s a substantial increment in the risk.

One thing we know is that earlier on in the phase of illness, people are much quicker to stop their medication. Most people, based on the data we have, will have some treatment interruption. But also, most people go back on treatment. As people are ill for a longer time, these interruptions tend to be less and less, which we interpret as people noticing that being off of medication is not helping them in the long run. And they must go back on treatment.

Kane: You published a paper on that in Schizophrenia Bulletin. Is that right?

Rubio-Lorente: Correct. Yes.

Kane: How many patients were involved in that study?

Rubio-Lorente: That’s a very large study, which encompasses the entire population of Finland over a span of two decades. It’s over 15,000 individuals with schizophrenia. And these were data we looked at very carefully. We used relatively advanced statistics to avoid confounding, and we are pretty confident that what we observed is actually real — that people very often stopped treatment soon after the first treatment, and then as they went back on treatment, they tended to stay on treatment longer and longer.

Kane: You’ve also talked about the role of nonadherence, and you said a few minutes ago how common it is. We need to emphasize that it is common not just in schizophrenia but in any chronic illness. It’s difficult to get people to take medicine on a regular basis. And we don’t have good methods for determining whether or not someone’s taking their medicine.

Rubio-Lorente: You’re right. This is not just schizophrenia. This is all over. This has been well studied. We know that people who have diabetes, hypertension, or any chronic condition that requires taking medicine every day usually have high rates of nonadherence. And this is often overlooked. We tend to trust too much our ability to tell who’s taking medicine and who isn’t. We know that we overestimate. The reality is that we don’t know. And most often, we would be surprised that people are not taking their medicines.

So, yes, that’s true in schizophrenia as it is in other conditions. But in schizophrenia, we’re lucky enough that even if we don’t have any good methods to tell at any given time whether or not someone is taking their medication, we have long-acting injectables, which, in a way, have the advantage of ensuring the delivery of medication for a period of time. In that sense, we are lucky we have these treatments that are not available for the conditions I just mentioned — hypertension and diabetes. There’s not a long-acting injectable hypertensive. That’s one of the advantages that we have in schizophrenia; however, it’s an underutilized resource. I think long-acting injectables could be used more in the clinic because the advantages are very clear.

Kane: How much data do we actually have in terms of those advantages? Have there been a lot of studies comparing long-acting injectable formulations to oral formulations?

Rubio-Lorente: There have been many studies, and I think it’s a very compelling case. I think the data is very clear, and this has been looked at in different ways and using different methods. For example, when it was looked at in clinical trials, the effect was not as large. Probably because that population — the population that goes into a clinical trial — is not so representative of the patients who would benefit most from these treatments. But once you get into studies that look more into real-world patients, then the effect is very, very clear. Just to give you an example, using this data set I made reference to, the Scandinavian data set, in a different study, the investigators found out that the risk for hospitalization while people were on a long-acting injectable was about one third less than when that same person was on an oral formulation. That’s just one piece of evidence. But I think it’s a very compelling case. I don’t think that, at this point, it is controversial. I think long-acting injectables are just clearly superior.

Kane: And there’s a recent paper by Kishimoto and colleagues in The Lancet Psychiatry that reviewed the three different methods for comparing long-acting vs oral medicine. And they reported that with each one of the methods, the results strongly favor the long-acting injectables. But as you said earlier, they tend to be underutilized. Why do you think this is?

Rubio-Lorente: I think there are a variety of reasons why these medications are underutilized. We tend to overestimate how much we can tell whether someone is not adherent or not. So, we don’t think of them as a tool that could help the patient we think is adherent. The reality is that, very often, we’re going to be wrong. Right? And a person we think is adherent actually is not consistently adherent. So, we overestimate our ability to tell nonadherence. We underestimate the rates of nonadherence, and that’s why many people don’t see the value in these drugs.

Also, some people feel that if they suggest to their patient to use a long-acting injectable, it conveys the message that they don’t trust the patient is going to take their medicine, and this may undermine the therapeutic relationship. I think this is a misconception, but I think it still happens. And the reality is that if you make it about the efficacy, and if you make it about getting people healthier, that’s why you should use a long-acting injectable.

Kane: We need to acknowledge that nonadherence is very common. It’s human nature to have trouble taking medicine. So if I’m so-called nonadherent, then my clinician needs to explain to me that this doesn’t mean I’m a bad patient or a bad person. It’s really human nature. We need to destigmatize nonadherence and be able to talk about how we make sure a patient is going to get the benefit of the medicine we think they need. And there are other advantages in terms of the long-acting medicine. We know exactly what the dose is. We can have good control over the dose. We also know when somebody stops taking it. So it gives us a chance to do something, call the family, or do a home visit. The person is protected from relapse for at least a little while after they stop taking the long-acting medicine. When they are on an oral medicine, this really doesn’t happen.

Rubio-Lorente: I completely agree. As we discussed, there are so many different reasons for using long-acting injectables. I can think of another one, which is the fact that these drugs have been conceived over decades as a last resort for people who have had multiple relapses and who have demonstrated left and right that they are not consistent taking their medications. I think we have to shift this paradigm into conceptualizing long-acting injectables as a tool that can prevent relapses.

The time when relapses are most common and most harmful is earlier on in the phase of treatment. As I was discussing earlier, the time in the course of treatment when treatment interruptions are most frequent is early on and after the diagnosis. So that’s when most relapses are going to occur, and that’s when people still have many things you don’t want them to lose. You want that person to be able to continue in a relationship, to continue with a job, and to continue in school. And this is really a critical window of opportunity — if you don’t prevent relapses during that period when the person still is developing, it’s going to have very bad consequences over the long term.

We have to reconceptualize these medications as something we should use very early on in treatment. They should be used prophylactically. We should be proactive about their use, not reactive. We should use them to prevent relapses, and not after relapses have already occurred. That’s a paradigm shift. I hope we think about these formulations differently over time, but it’s going to take some time to change the way people think about them.

Kane: The study we published in JAMA Psychiatry a couple of years ago about the PRELAPSE data suggests that if you work with the clinical team and you train them on the rationale for using a long-acting injectable — and also very importantly, how to have the conversation with the patient about the use of it — that most patients, even first-episode and early-phase patients, will agree to a trial of the medicine. In that study, we showed that patients who were treated at clinics that had undergone that type of training had a much lower risk for hospitalization than patients who were being treated in clinics with so-called usual care.

Another thing I wanted to ask you about is that your work has been very important in helping us understand the factors that might be associated with relapses that occur even when someone is taking medicine. For a long time, people have been trying to identify risk factors for relapse, given how important it is. But a lot of that has been confounded by the nonadherence you referenced earlier. Your work has really tried to eliminate that confounder. Can you tell us more about that? And then also tell us a little bit about what you’ve been finding with the neuroimaging strategy you’ve been using.

Rubio-Lorente: The idea is that, as we discussed before, nonadherence is going to be very difficult to identify at any given time. And also, it’s very prevalent. We think that about 50% of individuals with schizophrenia are going to be nonadherent to their medication at any given time. And that’s a big confounder. Whenever someone relapses, it’s very hard to know whether that person relapsed because the medication is no longer effective or because they stopped taking a medication that was previously effective. And that’s a critical difference. Because if it’s a matter of the medication not working, it’s probably due to different mechanisms [in a specific medication], and there are different ways to manage this. If it’s that the medication was not being used, then the intervention is different. You have to make sure the medication is used. So that was an important confounder.

The way to address that confounder and to be able to determine to what extent relapse happens because of nonadherence or because the drug is no longer being as effective as it once was, is to study relapse in individuals who are being treated for relapse prevention on a long-acting injectable. The reason is that we can tell exactly how much medication the person has been exposed to, and we know for how long or whether there were gaps. That way, if someone experiences a relapse while they were on a long-acting injectable medication and after they had been doing better on this medication, we can say quite confidently that it wasn’t because of nonadherence but because the person is not getting out of the drug the benefit they once were getting. That’s the concept. That’s the approach that we took to study — in particular, relapse despite ongoing treatment.

What we found is that looking at it from different angles — from the perspective of the entire population of Finland in one case, or looking at relapse prevention trials with long-acting injectables — using those two different methods, we found a similar result. The result was that somewhere between 10% and 30% of individuals who are adherent for a year with a long-acting injectable and who responded to it are going to experience some signs of relapse. It may not be so common in the clinic because, very often, people are not adherent to their medication for long enough. Right? What we typically see is that people stop the medication and then they relapse. But for those who maintain the use of their medication, we see that between 10% and 30% of them will have a relapse. This suggests that nonadherence is part of the issue, but it’s not the only problem. The problem is that it is possible that over the long run, these medications may not work for some individuals. And this goes along with some of the evidence I was alluding to before — that these medications over time may not be as effective, particularly after a relapse episode.

Using the paradigm of relapse on long-acting injectables, we are studying the mechanisms that could result in a mechanism that could explain why a drug that was previously effective is no longer effective over time. And we are at the very beginning of a series of studies. But essentially what we are doing is studying biomarkers of treatment response and relapse on antipsychotic medicine. If you think about it, it’s kind of like two sides of the same coin. Whatever biomarkers we can use for the prediction of treatment response may be related to the same mechanisms that lead to relapse despite ongoing treatment.

So, in a first series of studies, what we found was that, in fact, it’s true that people who have a relapse despite their long-acting injectable tended to have a biomarker that behaved a little bit more like sicker individuals, in the sense that there is a greater dysfunction of a region in the brain called the striatum. This suggests that what’s going on may be that these drugs can stabilize the function of the striatum, but over time, the individuals may not have this fixture from the medication on striatal functioning.

This is very preliminary work, and that’s why we are doing more research to try to find out whether it’s true or not. But that’s one of our hypotheses.

Kane: That’s a very exciting study because up until now, we really have not had good biomarkers to identify why some patients have relapse despite getting medication.

To summarize some of the points you’ve made, first, relapse is very common. Also, most patients, are going to experience a relapse. And in many cases, they will have more than one relapse. Particularly in the early phase of illness, these relapses can be quite devastating because they really interfere with social and vocational functioning and reduce the likelihood of recovery. So we have to work very hard to try to prevent relapse as early in the course of illness.

You commented on the potential role of long-acting injectable formulations reducing the risk for nonadherence and enabling us to provide more “guaranteed medication” to our patients. But you also emphasized that despite adherence, some patients will still relapse. It’s a much lower rate of relapse than it would be among patients taking oral medicine or patients taking no medicine at all. But there still are some patients who relapse. Utilizing patients who are receiving long-acting injectable medicine but relapse despite it gives you an opportunity to really study the mechanism underlying relapse. And you have some very exciting preliminary data related to resting-state striatal connectivity using MRI that may help us better understand why some patients relapse despite getting medication.

You’ve emphasized a lot of really important take-home points. Is there anything else you’d like to add?

Rubio-Lorente: I’ll just emphasize, as you said, that we have to take relapse very seriously. As doctors, we have to do a good job at trying to prevent relapse as early as possible. And that means talking to people about the fact that it’s going to be necessary to take medications for a long time in most cases. And the best way to do this is to use long-acting injectables. Now, it’s not easy to take medication. It’s not easy to take antipsychotics. And obviously these medications are not perfect. They still have side effects. They may not get rid of all of the symptoms. But I think it’s a matter of weighing the pros and cons and finding the right balance for each person to make sure they can prevent as many relapses as possible and have a life that’s as good as can be.

Kane: Yes, very, very well put. Good luck with your work. Very exciting. Thanks so much for joining us. This is Dr John Kane, for InDiscussion.



Schizophrenia Clinical Presentation

Natural Course of Schizophrenic Disorders: A 15-Year Follow-up of a Dutch Incidence Cohort

Predictors of Relapse Following Response From a First Episode of Schizophrenia or Schizoaffective Disorder

Five-Fold Increased Risk of Relapse Following Breaks in Antipsychotic Treatment of First Episode Psychosis

Long-term Continuity of Antipsychotic Treatment for Schizophrenia: A Nationwide Study

Real-World Effectiveness of Antipsychotic Treatments in a Nationwide Cohort of 29,823 Patients With Schizophrenia

Long-Acting Injectable Versus Oral Antipsychotics for the Maintenance Treatment of Schizophrenia: A Systematic Review and Comparative Meta-analysis of Randomised, Cohort, and Pre-Post Studies

Effect of Long-Acting Injectable Antipsychotics vs Usual Care on Time to First Hospitalization in Early-Phase Schizophrenia: A Randomized Clinical Trial

Psychosis Relapse During Treatment With Long-Acting Injectable Antipsychotics in Individuals With Schizophrenia-Spectrum Disorders: An Individual Participant Data Meta-analysis

The Pharmacological Treatment of Schizophrenia: How Far Have We Come?

Striatal Functional Connectivity in Psychosis Relapse: A Hypothesis Generating Study

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