Impact of 2025 REMS discontinuation on clozapine prescribing: An Interrupted Time Series analysis

Clozapine is the only FDA-approved treatment for treatment-resistant schizophrenia (TRS) but remains underutilized. In February 2025, the U.S. Food and Drug Administration (FDA) announced elimination of the Clozapine Risk Evaluation and Mitigation Strategy (REMS) program. The impact of this policy change on clozapine prescribing has not been empirically evaluated. Using the TriNetX US Collaborative Network, we identified 201,335 adults with schizophrenia or schizoaffective disorder between January 2024 and May 2026. Monthly incidence and prevalence of clozapine prescribing were calculated. Interrupted time series (ITS) analyses assessed changes in prescribing following the February 2025 policy change. Stratified analyses were conducted by age, sex, and race. Mean monthly rates of new clozapine prescriptions increased from 9.86 (SD 0.93) before the policy change to 14.99 (SD 3.49) afterward, while prevalence increased from 0.06 to 0.07. ITS analysis showed no significant immediate level change in incidence following the policy change (β = -0.52, 95% CI: -3.87 to 2.83; p = 0.751), but a significant positive post-policy slope (β = 0.76, 95% CI: 0.28-1.14; p = 0.002), corresponding to an increase from 12.14 to 26.45 per 10,000 person-months by April 2026. Age-stratified analyses showed no statistically significant post-policy slope changes, although the largest numerical increase was observed among individuals <25 years. These data indicate that clozapine REMS discontinuation was associated with a gradual increase in clozapine initiation but no immediate prescribing shift. Overall prevalence of clozapine prescribing remained low, suggesting that barriers beyond REMS continue to limit use and warrant targeted intervention and further investigation.