NP Notes: Treatment Approaches for Schizophrenia (SCZ Episode 4)

Craig Chepke, MD, DFAPA: Hello and welcome to the Great Exchanges in Schizophrenia podcast series. I'm your host, Craig Chepke. I'm a psychiatrist in clinical practice in Charlotte, North Carolina at Excel Psychiatric Associates and also the Scientific Director of Psych Congress. Joining me today is my friend and colleague Desiree Matthews. Desiree, tell us a little more about yourself for those who haven't heard of you before.

Desiree Matthews, PHMNP-BC: Thank you. My name is Desiree Matthews. I'm a board-certified psychiatric nurse practitioner and I have a telepsychiatry practice here in North Carolina. Prior to that, I spent eight years in community mental health treating a large proportion of my clients that had a diagnosis of either schizophrenia or schizoaffective disorder. So happy to be here today.

Craig Chepke, MD, DFAPA: Fantastic. So, today, I want to just introduce, kind of in broad brush strokes, the topics of pharmacological treatment of schizophrenia. So, Des, what types of antipsychotic medications are available to individuals with schizophrenia and how do they work or how do we think they work, at least?

Desiree Matthews, PHMNP-BC: How do we believe they work? That's a good point. So, we can probably first start with two big general buckets. We have our first-generation antipsychotics. The first one was approved back in 1954 actually. So, we've had a longstanding history of these medications that block dopamine or D2 receptors and parts of the brain, many parts of the brain, but we hopefully are blocking them in the striatum to reduce the positive symptoms associated with schizophrenia. We also have our second-generation antipsychotics. The first one approved was actually clozapine in 1989. I believe it was available on pharmacy shelves in 1990. After that, we had risperidone. That was approved in 1993 and is actually still listed as an essential medication by the World Health Organization. And, in addition to blocking D2  receptors, they also block serotonin 2A receptors. In addition to that, there's also three partial agonists that work at dopamine receptors.

Desiree Matthews, PHMNP-BC: So, we've had these medications since the 1950s now. In terms of other treatments, there are now muscarinic activators, an activator as well that was approved recently here this year in 2024. Clozapine certainly is, I would say, of its own class. It was originally, actually, I believe Craig, I believe it was discovered and synthesized in 1958. It went through clinical trials. But unfortunately, as we now know, because of the REMS program, they had deaths associated with agranulocytosis. So, that was actually halted. But luckily, the FDA did allow trials to resume, but the FDA actually had to prove that, had the company prove that clozapine was better than placebo and it was used and studied in treatment-resistant schizophrenia. So, these individuals had to have several failed trials of other antipsychotics in terms of adequate dose and duration. So, we have different option, not to mention the APA also recommends psychotherapy, psychoeducation for individuals living with schizophrenia as well as supportive employment services. So, it's not just medications when it comes to our treatment plan. We can think about the other add-on or adjunctive therapies that we have, and that's going to be a big one, is psychoeducation for me.

Craig Chepke, MD, DFAPA: Yeah, great point. While the main point of our discussion today is pharmacotherapy, we can't forget that it's not just about a medication. That people with schizophrenia do need psychoeducation and certain psychotherapies. There's also other interventions like cognitive remediation as a specific type of psychosocial type of treatment that has been shown to, for many individuals at least, to improve some of the cognitive deficits that individuals living in schizophrenia have. So, always definitely want to keep a holistic approach to schizophrenia. But turning back to the medications, I love how you call out clozapine as being basically in a different class. Technically, FDA labels it as atypical antipsychotic, but I agree it is a breed all of its own, the only medication approved for treatment-resistant schizophrenia, and also has the indication for reduction of suicidality in individuals with schizophrenia, which is another unique indication. And while it may bind to D2 receptors, we don't know how any antipsychotic works, but we sure as heck don't know how to clozapine works, but it probably is not by blocking the D2 receptors, but we'll leave that for another day. But what about the side effect profiles of the antipsychotics? What does that look like for different classes?

Desiree Matthews, PHMNP-BC: Yeah, absolutely. So, when we think about the first-generation antipsychotics, we saw certainly higher rates of drug-induced movement disorders. So, thinking about dystonia, akathisia, drug-induced parkinsonism, as well as our first-generation antipsychotics. If you look at the data, you're much more likely to develop tardive dyskinesia, which is really, at this point, something that tends to be irreversible once it takes hold. Some people spontaneously remit. But TD is certainly a long-term concern of individuals on these agents. Second-generation antipsychotics, you don’t—you're not scot-free from movement disorders. But, in general, we would say that they are less likely than our first-generation antipsychotics. However, you will still see that we need to monitor our patients for drug-induced movement disorders. And we also do have concerns metabolically. We can see weight gain, changes in glucose and lipid levels. With some antipsychotics, you can actually see elevations of prolactin or endocrine dysfunction with some of these medications. So, there's certainly a lot of warnings and precautions that we need to take into consideration to really individualize and personalize our choice of treatment based on the side effect profile as well as really what the patient needs in terms of delivery. Do we have an option for oral? Do they need maybe a long-acting injectable instead? So, it's really—needs to be personalized based on that individual.

Craig Chepke, MD, DFAPA: Absolutely. And so, actually when you first brought up tardive dyskinesia, my mind kind of fast forwarded to LAIs there. There was actually a retrospective study done out of Japan several years ago that was published, and these were spontaneously reported events of TD. So, there's caveats with this type of trial design, but it actually was able to show that there was an association of statistically—that was statistically significant lower rates of TD with LAIs compared to the equivalent, say, molecule of an oral medication. So, really fascinating there. Tell us a little more about the pros and cons of LAIs, Des.

Desiree Matthews, PHMNP-BC: Yeah, that's a great point out, Craig. Because we can see in meta-analysis looking at side effects that I think there's a perception that long-acting injectables may cause higher rates of side effects. But if you look at the literature, that's just not quite true. But I would say in terms of the pros for LAIs, let's put it out there, adherence. We know that individuals on LAIs, they are more adherent to treatment. They are less likely to relapse or have a delay in the time to relapse compared to their exact same oral counterparts of we're talking about paliperidone orally versus paliperidone LAI. We know that we see less risk of rehospitalization, we see less risk of relapse, and this is so important. I would say a con with our long-acting injectables is really options. You know, Craig, I love options as I know you do too, but we are limited by the active moiety or the compound in terms of our LAIs. We don't have quite as many to choose from as we do with our oral antipsychotics.

Craig Chepke, MD, DFAPA: Yeah, definitely true. And being a chemistry major in college, I love pharmacokinetics and pharmacology in general, and it's not for lack of pharmaceutical industry wanting to get more of the antipsychotics turned into LAIs. It's just not every molecule is amenable to becoming an LAI. And I believe probably every company who's ever made an antipsychotic has wanted to turn it into an LAI, but not all of them actually chemically will work that way, unfortunately. So, what patients are going to benefit the most from LAIs, do you think?

Desiree Matthews, PHMNP-BC: Oh, that's a good question. So, maybe I'm a little biased, but I offer all of my patients—and right now, those are early episode schizophrenia clients. I offer everybody LAIs because I think everybody could potentially benefit from a less frequent dosing interval. If you look at the APA guidelines for the treatment of schizophrenia, it does state that we should offer LAIs to everybody if they prefer treatment. So, we really have to talk to our patients, their families, about LAIs as an option because in there it says if they prefer treatment and if we don't talk to patients, their family, how do we know they have a preference? I don't think an 18-year-old is going to know all of their options. But also individuals that have a history of poor adherence on certain adherence. Maybe they're transitioning from say inpatient to outpatient or maybe from an ACT team down to traditional outpatient treatment, people that are potentially using substances, alcohol or otherwise illicit substances. This can make it harder for patients to adhere as well. But across the board, I think it's based on patient preference. But I honestly think anybody could benefit from an LAI.  

Craig Chepke, MD, DFAPA: Totally agree with you, and I do the same. I mean, it's just a standard thing that I offer for people with schizophrenia as a first-line option. I think about it like treating diabetes. There's the short term—short-acting insulin, and for a while that was all that they had. But then, longer-acting insulins were developed and having a once daily at the very least. And there are once-weekly options that are currently—some approved in Europe currently and being submitted to the FDA. But the body likes things to be pretty steady that having the ups and downs, even with the perfect adherence, that oral medications has a peak-to-trough ratio that is often relatively high. And LAIs have a consistent sustained delivery, and the body likes that kind of consistency and certainty, and that's something that oral medications just can't give to someone even if they are taken perfectly. And so, I think that, as you said, who couldn't benefit in some way, shape, or form from an LAI. And it's not just about adherence. Even people are perfectly a adherent—data that you mentioned earlier that there is a reduction in things like rehospitalization. There's data showing mortality improvements with schizophrenia in many studies, almost any outcome you can name, there is some evidence to support that it may be better with an LAI compared to its oral equivalent.

Desiree Matthews, PHMNP-BC: And thinking about patient preference, you know, I've heard from individuals living with schizophrenia that they prefer long-acting injectables because that they don't have to be reminded of their illness every single day. They don't have to kind of have that battle of, do I take my medication, do I not? Well, I feel okay, so maybe I won't take it today. So, there's a lot of internal dialogue that goes on with some individuals just with that daily battle of knowing they have to stop their day to take that medication. Also, I think if we talk to patients, we educate them. We actually have survey data that says once a patient starts an LAI that they actually wish their healthcare provider offered it to them earlier, that they felt better than their previous treatments. So, I think there's a lot of reasons to talk to patients and offer them. We can offer them anywhere from an injection every two weeks to once every six months. And I think that is just fantastic.

Craig Chepke, MD, DFAPA: Absolutely. You know, there's not an illness in the world whether it's schizophrenia, diabetes, COPD, asthma, whatever, that people aren't going to say at some point in their treatment, this sucks. I don't want to do this today. And they can get off course. Now, with schizophrenia, then a medication nonadherence can lead to a direct impairment in their ability to have that clear decision making to come back to treatment, which often does not happen with other types of illnesses. And so, what I love about LAIs is it's almost like an insurance policy for getting them back to treatment because with the very long half-life, especially those longer-duration LAIs, you mentioned the two-, three-, and six-month LAIs that even if they miss their scheduled injection, then they still have antipsychotic in their system for substantial length of time. And they can decide even if their last injection was due a week ago, a month ago, they can still decide, “You know, I am going to come back into the office and get my next injection.” And they don't have that same level of medication drop off from the steady state that they do with orals. So, that's a huge advantage in my mind when I'm discussing this with patients.

Desiree Matthews, PHMNP-BC: Oh, absolutely. And we can intervene. So, if they don't show up into our office, we can actually reach out and we know that they are missing their medication. As with oral medications, unfortunately, especially in community mental health, we wouldn't know a person stopped their oral medication or was partially adherent. So, maybe they were taking it a few times a week, relapsed. We wouldn't know until we got that patient scheduled for a hospital discharge appointment or maybe the jail is calling us and asking about their medication. So, at least with LAIs, we are—for certain, we know what they've gotten, we know when they've gotten it, and we can intervene if they miss their appointment, at least we can do something. As with oral medications, it's usually too late. They've already began experience a recurrence or had a full relapse of their schizophrenia.

Craig Chepke, MD, DFAPA: Such great points there, and I definitely love that as well, is that there's always going to be nonadherence. And technically LAIs don't necessarily improve adherence because they can not show up for the next injection. But that key difference that you've brought up—and I want to highlight that for our listeners—is that you know, as a provider, exactly when the nonadherence starts. Whereas with orals, you may not know until it's too late to intervene. They're already in the hospital. They're already in jail, and god forbid it could be that they're already in the morgue. And so with LAIs, at least lets us know for sure, hey, we need to do something now. So, that way, we can try to bring them back in before they suffer one of those adverse outcomes. So, that's a really important, I think, not well appreciated benefit of LAIs. So, thank you for bringing that up. So, unfortunately, we're out of time for today. But this was a great discussion and look forward to discussing more about LAIs in subsequent episodes. And I want to thank you for being with us today, Desiree.

Desiree Matthews, PHMNP-BC: Thank you so much.