Clozapine and Regulatory Inertia: Revisiting Evidence, Risks, and Reform.

In the United States, the Clozapine Risk Evaluation and Mitigation Strategy (REMS) program was implemented to ensure safe prescription and monitoring; however, its administrative complexity has often resulted in unintended barriers to access. Clozapine remains the most effective antipsychotic for treatment-resistant schizophrenia (TRS), yet its use continues to be constrained by outdated regulatory frameworks, cultural inertia, and clinical hesitancy. This perspective article revisits the pharmacokinetic foundations of clozapine, re-examines its association with fatal outcomes, and critiques the persistence of obsolete monitoring systems such as the U.S. REMS program. Drawing on recent consensus publications endorsed by over 120 international clozapine experts, this article outlines the proposed changes to the U.S. prescription information and contextualizes them within broader global practices. This article argues that many barriers to clozapine use stem not from evidence, but from regulatory conservatism and the perpetuation of clinical myths. The dismantling of the REMS program in early 2025 represents a pivotal moment, yet further reforms are urgently needed to align regulatory guidance with contemporary science. Ultimately, this article is a call to rediscover the clinical value of clozapine and to translate decades of knowledge into regulatory and clinical action.