Clozapine Remains Underused After REMS Elimination: A Conversation With Jose Rubio, MD, PhD

TALKING WITH TITANS

In this “Talking With Titans” episode, Psychiatric Times Editor in Chief, John J. Miller, MD, sits down with Jose Rubio, MD, PhD, to discuss why clozapine remains underutilized more than a year after the US Food and Drug Administration (FDA) eliminated its Risk Evaluation and Mitigation Strategy (REMS).

The FDA determined in February 2025 that the REMS was no longer needed to ensure clozapine’s benefits outweigh the risk of severe neutropenia, and all REMS operations ended June 13, 2025.¹ Prescribers no longer submit absolute neutrophil count (ANC) results before dispensing, although the agency still recommends ANC monitoring according to the label.¹

Rubio said advocates expected that removing the red tape would make prescribing easier, and in his impression it has. However, he does not believe it has produced a paradigm change, noting that good data on post-REMS use are still limited. He emphasized that clozapine is the only drug for treatment-resistant schizophrenia and has demonstrated anti-suicidal efficacy.

Reimbursement Barriers

Rubio identified reimbursement as a major remaining obstacle in 2026. Patients taking clozapine need blood monitoring and established pathways to internists, cardiologists, and hematologists when complications arise. Under fee-for-service billing, much of that overhead cannot be billed, creating a financial disincentive to use the drug. A national work group convened by state mental health program directors similarly flagged the lack of centralized infrastructure for coordinating clozapine-related services as a barrier to its use.²

Dedicated clozapine clinics offer one route to efficiency, Rubio said. Concentrating resources in one place, including staff to check labs and workflows for specialty referral, is easier than supporting patients scattered across a health system.

He proposed 2 broader solutions. The first is value-based arrangements that align payment with clozapine’s documented outcomes, including return to the workforce, reduced physical morbidity and premature mortality, fewer rehospitalizations, reduced suicidality, and independent living. The second is higher payments attached to billing codes used for patients taking clozapine, ideally through a simple, universal flag rather than workarounds that are difficult to scale. He suggested payers may be receptive, given potential savings on rehospitalization.

“I think it is a tragedy that we have things already in the market that give us all of these benefits, and we are not using them,” said Rubio.

Miller noted that the field is in a period of flux following the end of the REMS, and Psychiatric Times plans to follow up on how clozapine access evolves.

Dr Miller is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, Psychiatric Times; Volunteer Consulting Psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.

Dr Rubio is an assistant professor of psychiatry at The Feinstein Institutes for Medical Research. He also leads research operations from the Division of Psychiatry Research at Zucker Hillside Hospital, in coordination with clinical and neuroimaging services at Northwell.

References

1. Information on clozapine. US Food and Drug Administration. Accessed October 8, 2026. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/information-clozapine

2. Kelly DL, Freudenreich O, Sayer MA, Love RC. Addressing barriers to clozapine underutilization: a national effort. Psychiatr Serv. 2018;69(2):224-227.