Clozapine and Second-Generation Antipsychotics for Schizophrenia, with John Kane, MD

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The utility of second-generation antipsychotics and clozapine has been less advantageous than it could be, Kane explained.

Among the challenges hindering the pharmaceutical treatment of schizophrenia may be the very nomenclature used to describe its most viable agents.

In the second segment of an interview with HCPLive during the American Psychiatric Association (APA) 2024 Annual Meeting in New York, NY, this week, John Kane, MD, co-director and professor at the Institute of Behavioral Science at Feinstein Institutes for Medical Research, discussed the terminology and utility of second-generation antipsychotics for the treatment of schizophrenia.

When asked whether the nomenclature has a negative effect on the field, Kane declined, but added, “to some extent, it’s outlived its usefulness.”

“I think when the so-called second generation drugs were introduced, there was a lot of discussion, debate and research to determine how much better are they really,” Kane said. “I think one area where I believe there was a real advantage was in the reduction of some of the neurologic adverse effects.”

The prevalent risk of tardive dyskinesia due to first-generation antipsychotics, for example, is not associated with the second-generation glass. However, Kane noted, the latter class is associated with significant risk of metabolic events—a safety risk that newer drug classes are now improving upon.

“So, we've seen the evolution of new drugs that are better tolerated,” Kane said. “But what's been disappointing is we haven't seen the introduction of new drugs with clearly better efficacy. And as I mentioned a few minutes ago, I think it's been a little bit disappointing that clozapine remains the only such drug.”

In further discussing the low utility of clozapine to manage treatment-resistant schizophrenia, Kane noted it’s not a simplistic regimen—patient blood levels must be monitored, and a number of adverse event risks persist. Additionally, many guidelines recommend patients fail ≥2 antipsychotic doses for regimens of ≥6 weeks each before being considered candidates for clozapine.

“But what we see very often is that people go for years failing multiple antipsychotic drugs before they get a trial of clozapine,” Kane said. “And I think to some extent that's also related somewhat to the way clinicians perceive clozapine—that it's a hassle to use, that patients are going to resist the blood monitoring that's necessary.”

Part of this conflict comes in how clinicians present and discuss treatments like clozapine with patients, Kane said—a practice in line with shared decision making, but could lead to reduced buy-in on a viable schizophrenia treatment for patients who have failed all prior options.

“I think we've seen that there's room for implementation science, and that's really the study of, what does it take to change clinician behavior, to be able to introduce new research findings more rapidly into the clinic more more systematically?” Kane said. “You know, we've seen great variability in the utilization of clozapine, and of long acting injectable drugs from one clinic to another, from one state to another, from one hospital to another. And that just suggests that we're not doing as good a job of implementing guidelines as we could.”

It is currently estimated that 1 in 5 patients are exhibiting resistance to treatment at their very first episode of schizophrenia; adequate timing of care and utility of the most beneficial treatments are key in getting the condition managed responsibly.

“We don't have great evidence, but there's some evidence suggesting that if you wait more than a couple of years before introducing clozapine, it's not going to be as efficacious as it would have been if you had introduced it earlier,” Kane said. “So you know, we have a lot of work to do in that regard.”

Kane is a consultant and/or has received honoraria from Alkermes, Allergan, Boehringer-Ingelheim, Cerevel, Dainippon Sumitomo, H. Lundbeck, HealthRhythms, HLS Therapeutics, Indivior, Intracellular Therapies, Janssen Pharmaceutical, Johnson & Johnson, Karuna Therapeutics, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Newron, Novartis, NW PharmaTech, Otsuka, Roche, Saladax, Sunovion, Teva.