Antipsychotic Exposure and Pharmacologically Treated Type 2 Diabetes in Dutch Youths

Importance: Antipsychotic medications are widely prescribed to children and adolescents worldwide, raising concerns about treatment-emergent type 2 diabetes (T2D). Previous studies have reported elevated T2D risks but have relied on between-person comparisons susceptible to unmeasured confounding and have not characterized risk trajectories around treatment initiation. Objective: To determine the annual prevalence of pharmacologically treated T2D before and after antipsychotic initiation in Dutch youths. Design, Setting, and Participants: This cohort study used data from Dutch population-based registers to track yearly pharmacologically treated T2D prevalence up to 5 years before and after antipsychotic initiation among youths aged 0 to 19 years initiating such medication. Using fixed-effects models, the event study design controlled for all stable, person-specific confounders that limit standard between-person comparisons. Data were collected from January 1, 2006, to December 31, 2022, and analyzed beginning in February 2025. Exposure: Antipsychotic initiation (first recorded dispensation). Main Outcome and Measures: The primary outcome was annual prevalence of pharmacologically treated T2D, defined as at least 1 dispensation of a noninsulin glucose-lowering medication within a given year. Annual risk differences (RDs) and relative risk changes were estimated using the year preceding antipsychotic initiation as the reference. Results: A total of 89 991 youths who were dispensed at least 1 antipsychotic prescription between 2006 and 2022 (median [IQR] age at antipsychotic initiation, 13.6 [9.8-16.7] years; 55 794 [62.0%] males) were included in the sample. In this cohort, pharmacologically treated T2D prevalence was stable before treatment and increased significantly after antipsychotic initiation. The RD increased from 2.47 (95% CI, 1.09-3.86) per 10 000 antipsychotic users in the initiation year to 9.02 (95% CI, 5.99-12.06) per 10 000 users by year 5. Females had greater absolute excess risk of T2D than males by year 5 (RD, 16.48 [95% CI, 8.95-24.00] per 10 000 users vs 5.50 [95% CI, 2.57-8.43] per 10 000 antipsychotic users). Adolescents aged 13 to 19 years had a larger long-term increase in risk than children aged 7 to 12 years (year-5 RD, 14.09 [95% CI, 8.19-19.98] per 10 000 users vs 5.47 [95% CI, 2.76-8.18] per 10 000 users). While recurrent users experienced greater, progressively increasing risk (RD, 10.17 [95% CI, 6.47-13.87] per 10 000 antipsychotic users by year 5), elevated risk of pharmacologically treated T2D persisted among youths using antipsychotics in the initiation year only. Conclusions and Relevance: In this within-individual cohort study, antipsychotic initiation in youths was associated with a rapid, sustained increase in treated T2D risk independent of underlying time-invariant factors. These findings indicate that even brief antipsychotic exposure is associated with a sustained metabolic vulnerability, underscoring the need for routine metabolic monitoring and preventive strategies from antipsychotic treatment initiation.