John M. Kane, MD: I guess as we suggested, one of the biggest obstacles is communicating this to the patient. And in my opinion, this is something that should start pretty early in the illness—that once you’re having that psychoeducation discussion with a patient about the nature of the illness, the fact that medication is very important in managing the illness and preventing relapse. Once we accept the fact that medication is important, why not turn to an alternative that provides guaranteed medication so we can be confident that the person is actually getting the benefit of the treatments that we’ve developed?
And I think patients, if it’s explained in the right way, can be very receptive to that concept. I think the sooner we introduce it, the more it becomes an expectation of the treatment plan. When somebody leaves the hospital, and 6 months later or 12 months later someone suggests, “Well, maybe we should try a long-acting drug,” I think that might be less likely to succeed than if it’s presented to the patient as, “This is the way we treat your illness. First, we’re going to start with oral medicine. We’re going to see how you tolerate it. We’re going to make sure you respond. We’re going to switch you to a long-acting formulation, and that’s what you’ll be on when you’re out of the hospital.” I think that may work much better.
T. Scott Stroup, MD, MPH: In first-episode psychosis, this is the one place where there’s a pretty good randomized controlled trial [RCT] showing some advantages of shots over pills, right?
John M. Kane, MD: Yes.
Jeffrey A. Lieberman, MD: You’re talking about the UCLA [University of California, Los Angeles] study?
T. Scott Stroup, MD, MPH: Yes, the UCLA study. There was a pretty dramatic reduction, which is a real outlier compared to these other studies. I’m not quite sure why that is, but it’s a legitimate RCT.
John M. Kane, MD: Yes, and there are attempts to replicate that. Interestingly, in that study, they also found an increase in cortical myelination among the patients receiving the long-acting formulation of risperidone compared to the patients receiving the oral formulation of risperidone, which is a very interesting finding that needs to be replicated.
T. Scott Stroup, MD, MPH: I do think there’s something about being able to adjust the doses sort of quickly in these people who are being exposed to antipsychotics for the first time, just to avoid bad experiences.
John M. Kane, MD: Right. So you wouldn’t necessarily want to start someone on a long-acting formulation. You’d want to start with an oral agent, get the dose right, and make sure it’s a minimum effective dose; but then potentially transition to a long-acting formulation?
T. Scott Stroup, MD, MPH: Pretty quickly.
John M. Kane, MD: Yes. But that leads into another question about the dose adjustments. So you were just saying it’s easier to adjust dose with an oral medicine. Do you think that will interfere with our ability to optimally use the long-acting formulations? Because we can supplement with oral if we have to, right?
T. Scott Stroup, MD, MPH: That’s true. I think initially, when you’re trying to find the right dose and avoid too many adverse effects, I’m not a big believer in micro-adjusting as you go on. I think once you find a dose that works, there’s less of an issue with problems with long-acting injectables [LAIs], in that way. But I don’t typically adjust the dose every visit if there’s a slight issue.
John M. Kane, MD: Right. Jeffrey, what do you think? Are there any disadvantages to long-acting injectable formulations?
Jeffrey A. Lieberman, MD: No. I think that the fact that we don’t use them as much or more often than we do, analogous to the underutilization of clozapine—there’s no excuse for it. It’s an embarrassment to our field that we don’t. There may be deterrents. “Oh, we don’t have a nurse. We don’t have the infrastructure. We don’t have this. Blood draws and these WBC [white blood cell] levels are a pain.” Those are excuses.
There’s no disadvantage, and there’s potentially considerable advantages. The main one, of course, is adherence. It facilitates adherence. But even beyond that, it may be a more effective mode of delivery of antipsychotic medicine because you don’t have the peaks and troughs. You don’t have as much in the pharmacokinetic variation with the blood levels of the drug. The substance in which it’s esterified with or is formulated with facilitates penetration into the blood-brain barrier as well. And so, there’s no downside. It’s just the pragmatics of, as you say, educating people to overcome the aversion to injections and whatever the hassle is. It would be great to build it into a process of orienting patients to what the logical sequence of their treatment would be, including the convergence to LAIs. But how many guidelines have you seen where that’s part of the recommended process?
John M. Kane, MD: I think the guidelines actually have been a little weak, in all honesty. Because if you look at the guidelines, they kind of suggest that you want to see multiple relapses before you consider an LAI, which I think is really misguided. Why would you want to see multiple relapses? I think we want to try to prevent as many relapses as possible. But there are still many clinicians out there who say, “Well, I will assume that the patient is adherent until they show me that they’re not.” And the only way that we learn that someone’s nonadherent is when they get sick again. So it’s an unfortunate way to learn, and I think that there’s still a little bit of a disconnect there.
Jeffrey A. Lieberman, MD: Maybe we should use contingency reinforcement to physicians to prescribe LAIs?
John M. Kane, MD: Well, that’s no joke. Because if we agree, and as Scott suggested, that both clozapine and LAIs involve perhaps a little more effort and a little more hassle, some clinicians would say, “I’m not incentivized to spend more time doing this.”
Jeffrey A. Lieberman, MD: Yes, that’s a good point John. We shouldn’t be so tough on our colleagues. Look at the infrastructure by which mental-health care is provided in many places. You’ve got a doctor with a lot of paraprofessionals, and the doctor’s got about 10 minutes to see a patient and go through the whole process of evaluation and then prescribe. It doesn’t facilitate the optimal level of care, including how we should be able to introduce other modalities like LAIs.
T. Scott Stroup, MD, MPH: Again, you’re reminding me of the analogy to clozapine. Going serially through lots of oral medications, there’s no real benefit for doing that. I mean, changing medications helps you get away from adverse effects, but does it really get you to better efficacy or adherence? So I think pretty quickly you should be considering long-acting injectables or clozapine. I think you can debate which one of those should come first.
Jeffrey A. Lieberman, MD: John, which country do you think comes closest to using them in an optimal way?
John M. Kane, MD: From the last data I saw, I know Spain had an increase in utilization rates. But I haven’t seen any recent data. I think most countries around the world are still using them less than they should be. It’s the same with clozapine. It’s interesting. As you said, there are really strong analogies between these 2 options. And maybe it’s training. If you talk to some of the residents who’ve trained in places where LAIs are not widely used, they’re not as comfortable. If you talk to residents who’ve trained in places where they don’t use a lot of clozapine…. I think we have to make sure that’s part of the training.