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Introduction: Use of antipsychotic drugs, especially second-generation agents, has been suggested to cause acute pancreatitis in multiple case reports; however, such an association has not been corroborated by larger studies. This study examined the association of antipsychotic drugs with risk of acute pancreatitis.

Methods: Nationwide case–control study, based on data from several Swedish registers and including all 52,006 cases of acute pancreatitis diagnosed in Sweden between 2006 and 2019 (with up to 10 controls per case; n = 518,081). Conditional logistic regression models were used to calculate odds ratios (ORs) in current and past users of first-generation and second-generation antipsychotic drugs (dispensed prescription <91 and ≥91 days of the index date, respectively) compared with never users of such drugs.

Results: In the crude model, first-generation and second-generation antipsychotic drugs were associated with increased risk of acute pancreatitis, with slightly higher ORs for past use (1.58 [95% confidence interval 1.48–1.69] and 1.39 [1.29–1.49], respectively) than for current use (1.34 [1.21–1.48] and 1.24 [1.15–1.34], respectively). The ORs were largely attenuated in the multivariable model—which included, among others, alcohol abuse and the Charlson comorbidity index—up to the point where only a statistically significant association remained for past use of first-generation agents (OR 1.18 [1.10–1.26]).

Conclusion: There was no clear association between use of antipsychotic drugs and risk of acute pancreatitis in this very large case–control study, indicating that previous case report data are most likely explained by confounding.