Peter L. Salgo, MD: Now we come to the difference between oral and injectable formulations. In 1 case, the orals, it’s up to the person with this problem to volitionally take these pills.
John M. Kane, MD: Every day.
Peter L. Salgo, MD: Every day.
John M. Kane, MD: That’s right.
Peter L. Salgo, MD: Injectables, not so much.
John M. Kane, MD: Right.
Peter L. Salgo, MD: What are the injectable formulations out there? How long do they last?
John M. Kane, MD: We have a range of formulations now, anywhere from every other week, once a month, once every other month, to once every 3 months. There’s really a range of options, and I think people are going to vary in terms of what they think is best for them. Obviously, they’re going to work with the clinical team to decide the best approach. But as you suggested, the difference between taking pills every day, where you have to make a conscious decision to take the medicine—you have to remember to take it, you have to be organized to take it, you have to have it in your possession—is so different from having someone give you an injection once a month or once every 2 months. That’s a completely different scenario.
Peter L. Salgo, MD: So adherence is better with the injectables.
John M. Kane, MD: Adherence is much better, and not only is the adherence better, but it puts the clinical team in a completely different position in terms of knowing whether you’re taking your medicine. This has been shown in many research studies that clinicians will usually overestimate the degree to which their patients are taking their medicine because we all think we’re great doctors, and we have terrific therapeutic relationships.
Peter L. Salgo, MD: Well, I am. I don’t know about you, but I’m perfect.
John M. Kane, MD: Well, we actually did a study in which we asked doctors, “What do you think the average rate of compliance is based on the literature?” These were experts in the treatment of schizophrenia. What do you think the average rates of compliance are based on the literature? They gave us a number, and we said, “Well, what about among your patients?”
Peter L. Salgo, MD: Oh.
John M. Kane, MD: Needless to say, the latter was a much higher estimate than the former. I think we all have this narcissistic attitude that our patients are going to be adherent, because of course, we’re, you know.
Peter L. Salgo, MD: We all live in Lake Wobegon.
John M. Kane, MD: Absolutely.
Peter L. Salgo, MD: All the women are beautiful, all the men are tall, and all the children are better than average.
John M. Kane, MD: Absolutely, and everyone is adherent.
Peter L. Salgo, MD: Everyone is adherent.
John M. Kane, MD: I think this has been shown in so many studies. One of the challenges is that physicians have to realize that they are not very good at determining whether their patients are adherent. Because what do they do? They ask the person, “Are you taking your medicine?” The person may not even remember when they’ve missed it or when they’ve not missed it. It’s not that our patients are lying to us. They often just don’t really know whether they take it.
Peter L. Salgo, MD: The capacity among human beings for self-delusion is infinite.
John M. Kane, MD: Yes, absolutely.
Peter L. Salgo, MD: The other part of this is when you get to the end of the month, you have to refill that script. And maybe the pharmacy is closed, you forgot, the insurance company has changed the formulary, and now you need a different brand name or a generic. It’s a hassle.
John M. Kane, MD: That’s right. All those things come into play. But in addition to improving the likelihood of adherence, we’re also improving the likelihood that the clinical team knows what’s going on. One of the things we experience when a patient comes to the emergency department in a psychotic state is we’re going to ask ourselves, “Well, was he or was she taking the medicine as prescribed or not?” That’s very important information. We did a study in which we actually drew blood levels of the antipsychotic drug when people came to the emergency department. We compared the results of the blood level assay to the opinion of the doctors who evaluated the patient.
Peter L. Salgo, MD: That’s a nasty test.
John M. Kane, MD: It’s a nasty test, and needless to say there was not good agreement. That’s a critical decision point for the clinical team, that your actions, your recommendations, are going to be very different if you know that the patient relapsed because in actuality, they either were or weren’t taking the medicine.
Peter L. Salgo, MD: If you take a look at the injectables, is it fair to divide them into various classes—shorter-acting, medium-acting, and then longer-acting?
John M. Kane, MD: As you said, the interval varies, so you might have a drug that is given every other week, every 4 weeks, every 8 weeks, or every 3 months. That’s based on the pharmacokinetics of specific drugs. The great thing is that we have some choices.
Peter L. Salgo, MD: Let me use a nonprecise term. I’m going to use the term efficacy, and I don’t mean this statistically. I don’t have a P value for it. But if you have a long-acting injectable versus a shorter-acting injectable, what is the efficacy comparably? Is it better to give 1 shot for—you said 3 months was 1 of the newer ones?
John M. Kane, MD: There’s no difference in the overall effectiveness in terms of preventing relapse. Let’s put it that way. But 1 advantage of the longer interval is that if the patient misses an injection, they can go for a longer period of time until their next injection. That’s helpful because I think 1 of the advantages of the long-acting formulations, as I said before, is that we know whether the patients received it. This is because if they don’t receive it, we actually have some time to intervene, and we can call the family or significant other. We can do a home visit. We can do whatever is necessary. When someone stops taking their oral medicine, we have no idea. We don’t know, and it’s out of their system pretty quickly.
Peter L. Salgo, MD: Based on what you told me, it seems that the risk of relapse is lower, not because the risk of relapse is any different when the medications are all gone, but the risk is lower with the longer-acting injectables because you have more time to regroup.
John M. Kane, MD: Right. If you look at it that way, and if you’re including the period of time after it stopped, then yes, that would be true. But during the time that someone is actually receiving their injections as prescribed, we don’t see a difference.
Peter L. Salgo, MD: The risk of relapse with the longer-acting injectables compared with oral agents, again, not while on the medications but over the whole gamut. My guess is, from what you’ve told me, the risk of relapse is much lower with the longer-acting drugs because they’re on the drugs more reliably, more predictably.
John M. Kane, MD: Yes. There are different methodologies that have been used to study that, but in my opinion, the data are pretty overwhelming that the risk of relapse and rehospitalization is lower with the long-acting formulations than with the oral drugs. There are a few randomized controlled trials that don’t show that. But 1 of the problems when you do a standard RCT [randomized controlled trial] is that the participation in the trial itself really changes the ecology of care. So you’re now in a clinical trial, you’ve signed a consent form, and you’re being assessed frequently. You have now a relationship with the research assistant. The research coordinator calls you on the phone and reminds you of all these things. When you’re studying adherence, I think you have to be very careful that the study itself doesn’t change.
Peter L. Salgo, MD: But studies always change everything.
John M. Kane, MD: They do.
Peter L. Salgo, MD: Study patients always do the best.
John M. Kane, MD: No, that’s true and they get the best care in my opinion.
Peter L. Salgo, MD: Sure.
John M. Kane, MD: But there are other ways of looking at it. You can do naturalistic cohort studies with large databases. You could do mirror image studies. Those approximate better what goes on in the real world. You can do large, simple trials. When we do those kinds of studies, the results are pretty compelling favoring the long-acting injectable formulations.
Transcript edited for clarity.