LAI Antipsychotics: Treatment Selection in Schizophrenia

Considerations for selecting an appropriate long-acting injectable antipsychotic for the treatment of a patient with schizophrenia.

John M. Kane, MD: One of the things that discourages people is that it’s so complicated to switch. I hear people say, “I have someone on oral medications and I’ve got the dose right, and now you’re telling me I should switch to a long-acting formulation? I don’t know exactly how to do that.” Is that a concern?

T. Scott Stroup, MD, MPH: It’s not a concern that I think is real. I remember all these tables about converting from 10 mg a day of fluphenazine to whatever it was. I found that complicated, and I found it easier just to have a target dose that you think might work. So I don’t think it’s that complicated.

John M. Kane, MD: And I think what you’re doing is you’re making an investment in a long-term treatment. So if it takes a little time to titrate or to supplement with oral medication, if you have to for a couple of weeks, you’re making this effort for a reason that hopefully will be advantaging the patient over the long term.

T. Scott Stroup, MD, MPH: With some of the medications it is clearly recommended that you have cross titration, but frankly, I think it’s a good idea for all of them.

John M. Kane, MD: Well, now we have choices also. We have different formulations. Some require supplementation, and some don’t. Some have loading doses, and some don’t. So there are many more choices. People need to read the package insert, learn about a compound, and learn how to use it.

We talked a little bit before about the second-generation drugs. I remember years ago hearing, after the introduction of the second-generation drugs, that people were saying, “I’m not using an LAI [long-acting injectable] because I don’t have a second-generation LAI.” We just had haloperidol and fluphenazine. Now we have a whole range of second-generation LAIs, so that’s no longer a reason not to use them. But we’re still struggling with this. We talked earlier about some of the potential advantages of the second-generation drugs, in terms of reducing neurologic adverse effects. But we still have concerns about some of the metabolic adverse effects.

One of the questions that comes up frequently is, how do you decide which long-acting formulation to use? And my response to that is, we have several now. We have risperidone. We have paliperidone. We have olanzapine. We have aripiprazole. We have intramuscular. We have subcutaneous. We have injections that can be given every 2 weeks, every 4 weeks, every 6 weeks, every 8 weeks, every 3 months. They’re working on an every-6-month formulation.

So there are lots of choices. At the end of the day, it comes down to the clinical team deciding what’s the best drug for a particular patient based on past history, past response, sensitivity, the adverse effects, and what have you; and then hopefully seeing that the drug is available in a long-acting formulation and working on a treatment plan. For instance, we’re going to use the oral medications first. We’re going to establish the right dose and then we’re going to switch. And I think having choices is a tremendous advantage. Patients and clinicians and families now have lot of options.

T. Scott Stroup, MD, MPH: I think in oral medications you choose based on adverse effects, basically. With these, there are a few other parameters here: the distance, the length of time between the shots. I do feel obligated to put in my pitch here for our study that compared long-acting paliperidone to long-acting Haldol. They both worked very well. They had different adverse effect profiles. Predictably, Haldol had a little more on the neurologic adverse effects and the newer medication had more weight gain, but they both worked very well. And you know, that’s another axis. Haldol is a lot cheaper. If you have insurance, I’d probably go for one of the newer medicines too, but it’s a….

Jeffrey A. Lieberman, MD: Your study showed that the difference was adverse effects, so it’s, in some ways, choose your poison.

T. Scott Stroup, MD, MPH: It is. That was in the editorial about study. It said, “This is the evidence. Even for these medications, it is pick by adverse effects.” I’m not disputing that.

Jeffrey A. Lieberman, MD: Well it would be nice to have a comparative effectiveness study for the newer medications.

T. Scott Stroup, MD, MPH: Between the newer medicines.

Jeffrey A. Lieberman, MD: Yes.

John M. Kane, MD: I still worry about tardive dyskinesia. Obviously, that’s something that we spend a lot of time studying. The data are not great, because we don’t do long-term randomized studies. But what we’ve seen in the analyses that we’ve done is that the rate of the incidence of tardive dyskinesia is about one-fifth with the newer drugs compared to what it was with the older drugs. You need a big study to show that, and you need patients who are vulnerable to developing tardive dyskinesia. So obviously there are tradeoffs, but I guess I’m still in favor of the second-generation drugs for that reason.

T. Scott Stroup, MD, MPH: Yes.

John M. Kane, MD: But we have the weight gain.

T. Scott Stroup, MD, MPH: There’s a tradeoff. And I will say that for the Haldol/paliperidone study that we did, which Dr McEvoy was the lead author of, it was a fairly long study. It was 18 months, or actually even up to 2 years. It was up to 2 years, and we didn’t get much of a signal on abnormal involuntary movements. We got a signal on akathisia.

John M. Kane, MD: Right.

Jeffrey A. Lieberman, MD: But I don’t the import of the study, or what you’re saying Scott, is to advocate for first-generation versus second-generation because the main difference was economic. And the thing is that you don’t know what the comparative effectiveness is if you don’t do the study. And so, it would be good to know how aripiprazole, how Invega Sustenna, or is it [Invega] Trinza, compare. The other thing is that with TD [tardive dyskinesia], are there data about TD incidence for people on long-acting versus oral?

John M. Kane, MD: Yes, there are. That was one of the questions that people had, because initially there were some studies that suggested that maybe the incidence was higher on LAIs. But the problem there is you have a confound of nonadherence.

Jeffrey A. Lieberman, MD: Right.

John M. Kane, MD: And actually, there are some studies suggesting that the intermittent use of antipsychotic drugs may be more deleterious in terms of the evolution of abnormal involuntary movements than continuous exposure. The nice thing about long-acting injectables is they not only ensure continuous exposure, but we can also be very confident that the patient is getting the dose that we intended. You mentioned early some of the studies that we did trying to find minimum effective dose. In all of those studies we used long-acting injectable formulations, because you don’t want to go down to a micro dose with the possibility that the patient might miss a few doses, and then you kind of don’t know where you are.