Emerging Therapies & Strategies in Schizophrenia

John M. Kane, MD: That’s a good segue into discussing what some of the new drugs on the horizon are. Is there anything that’s really exciting that you might want to see in a long-acting formulation?

Jeffrey A. Lieberman, MD: I think the 1 that looks like it’s the most imminent is lumateperone from Intra-Cellular [Therapies, Inc], previously known as ITI-007. It’s an antipsychotic that does have affinity for the dopamine 2 [D₂] receptor, so it has kind of the price of entry to antipsychotic efficacy. But it has other pharmacologic properties, ostensibly, that are believed or hoped to confer 1) either superior efficacy or 2) a favorable adverse-effect profile. The phase 2 and the phase 3 data, at least on the adverse-effect profile, look quite promising. Superior efficacy remains to be seen. Given the fact that its adverse effects seem very good, and that it seems to work, that would seem to be a candidate for a long-acting formulation. I don’t know what the medicinal chemistry challenges are to doing it, but that would be 1 that would be desirable.

T. Scott Stroup, MD, MPH: As you were saying, if there is something else that works for treatment- resistant schizophrenia, that would be…

John M. Kane, MD: Sure.

Jeffrey A. Lieberman, MD: Yeah.

John M. Kane, MD: Are there other compounds on the horizon that look interesting?

Jeffrey A. Lieberman, MD: There are, but you have really a distinction between me-too drugs that are just variations on a D₂ receptor, pharmacodynamic effects, and innovative nondopamine-targeted treatments like xanomeline, for example. Xanomeline is a muscarinic partial agonist for the 1 [M₁] and the 4 [M₄] receptor subtypes. It was studied some years ago by Eli Lilly & Co, initially for Alzheimer, and was found to be most effective for the psychosis and agitation as opposed to the cognitive impairment. But it had adverse-effect problems, so they tried using it with schizophrenia. The first study they did was quite promising, but they lost interest, ostensibly because of adverse effects. But who knows?

At any rate, some years later, it has now resurfaced. It’s being developed by a company called Karuna [Pharmaceuticals, Inc]. It’s being developed with a combined antidote to the adverse effects. So it’s like, remember the old trilafons?

John M. Kane, MD: Sure.

Jeffrey A. Lieberman, MD: It’s a combination of xanomeline plus something called trospium, which would inhibit some of the peripheral adverse effects. So that looks very interesting, but I think the first hurdle is that it has to show that it’s a bona fide antipsychotic. And then if it is, it will be the first nondopamine-acting compound that has antipsychotic effects. We’ll see about its ability to be formulated in a long-acting way.

John M. Kane, MD: Any other drugs?

Jeffrey A. Lieberman, MD: There are a lot of drugs that are out there. There’s the glutamate-targeted drugs, like pomaglumetad. A company called Taisho [Pharmaceutical Holdings Co, Ltd] in Japan has TS-134, which is similar in pharmacology to pomaglumetad, an mGluR 2/3 [metabotropic glutamate receptor group 2 and 3] partial agonist, which inhibits the release of glutamate. Sunovion [Pharmaceuticals Inc] has a drug that is a trace amine—receptor inhibitor. And there’s phosphodiesterase [PDE]. You take your pick. PDE isoforms come in, like, 12 varieties. So there’s a PDE9 that Boehringer Ingelheim has that’s being studied for its putative antipsychotic effects. But you, as much or more than any of us, have seen these so-called novel mechanisms come and go, and not 1 has sort of passed the test. I wouldn’t place any great hopes on the likelihood. Lumateperone is a definite. We’re going to have it and can see how it does. And if it’s good, then that would be a prime candidate for a long-acting formulation. The others that are the more novel mechanisms—I think we just have to wait.

T. Scott Stroup, MD, MPH: What about this antipsychotic that was approved for Parkinson disease, pimavanserin?

Jeffrey A. Lieberman, MD: It’s not an antipsychotic. It’s a 5-HT_2A antagonist.

T. Scott Stroup, MD, MPH: How did they get it approved? Does it work?

Jeffrey A. Lieberman, MD: No comment.

T. Scott Stroup, MD, MPH: There’s no role for it in schizophrenia.

Jeffrey A. Lieberman, MD: Not in my opinion.

John M. Kane, MD: There are people suggesting there might be, but to be continued. That’s a good segue into nonpharmacologic strategies, also. Are there new things that we have to offer patients in terms of treatment? I would point to coordinated specialty care as an attempt to integrate different modalities into the treatment of first-episode and early-phase schizophrenia. I think that has shown some promise. I don’t think it’s surprising that if we can provide good psychosocial treatment, along with good medication, that’s going to help patients in the long run, particularly during the early stages of the illness, when we want to also work with the families and make sure that people can get back to school or back to work. I don’t know if I can say that has been a new advance, but I think we’re perhaps getting better at doing that and implementing that into clinics.

T. Scott Stroup, MD, MPH: I mean, it seems like a great idea to have comprehensive plans to help prevent disability in the first place. That’s really good. I wish they weren’t restricted to first-episode people, though.

John M. Kane, MD: Right.

Jeffrey A. Lieberman, MD: I think it’s an advance that’s really a model of disease management. But then look at ACT, assertive community treatment. I mean, we’ve known for years that it’s effective, and it’s effective in the same population that LAIs [long-acting injectables] have been targeted to. But it hasn’t caught on. That’s an infrastructure problem.

John M. Kane, MD: Is that a reimbursement issue?

Jeffrey A. Lieberman, MD: Yeah. I mean, infrastructure follows financial incentives. If there were revenue streams—if Medicare and Medicaid and whatever some number of third-party private insurance companies were reimbursing whatever the constituent elements of that are or the service as a whole—that would be out there. I mean, that would be available, but it’s not because it hasn’t been, and that’s kind of a financing system and policy problem. Is there anybody who doubts that ACT is effective?

T. Scott Stroup, MD, MPH: I think it has been proven again and again to help reduce relapse rates, for sure.

John M. Kane, MD: We know that health care can be improved in many, many ways. Our system is perhaps too focused on acute treatment and not focused enough on prevention and disease management. That applies not just in psychiatry but really much across the board.

Transcript edited for clarity.