Multidimensional Assessment of Psychiatric Adverse Events Related to Proton Pump Inhibitors: A Real-World, Pharmacovigilance Study

CNS Neurosci Ther. 2025 May;31(5):e70436. doi: 10.1111/cns.70436.

ABSTRACT

INTRODUCTION: Limited research has been conducted on the association between proton pump inhibitors (PPIs) use and psychiatric adverse events (AEs), leaving the understanding of PPIs-related psychiatric AEs in real-world settings unclear.

OBJECTIVES: We aim to identify psychiatric AEs highly relevant to five commonly prescribed PPIs and to delve into the clinical characteristics of the population experiencing psychiatric AEs, as well as the time-to-onset pattern of the reported AEs.

METHODS: We performed disproportionality analysis to evaluate the PPI-related psychiatric AEs risk signal using data from the FDA adverse event reporting system. Linkage disequilibrium score regression, high-definition likelihood, and Bidirectional MR analyses were employed to evaluate genetic correlations and causality for the pairwise traits between indications for PPI therapy and three common psychiatric disorders.

RESULTS: Psychiatric AEs were reported in 12.83% of all AE reports on PPIs. Disproportionality analysis identified multiple PPI-related psychiatric AE risk signals such as depressive disorder, bipolar disorder, and sleep disorder, with Omeprazole exhibiting the highest number of positive signals and cases (N = 386) and Rabeprazole the fewest (N = 28). Notably, we detected positive signals for suicide or self-injury-related AEs in three types of PPIs. Significant genetic correlations were revealed in peptic ulcer with major depressive disorder, peptic ulcer with schizophrenia, and gastroesophageal reflux disease (GERD) with major depressive disorder. Bidirectional MR analyses identified significant causal relationships between MDD and peptic ulcer, and a potential bidirectional causal association between GERD and MDD.

CONCLUSIONS: PPI-related psychiatric AEs may represent a non-negligible portion of overall PPI-related AEs. It is recommended to monitor and evaluate the safety of long-term PPI use in relation to psychiatric AEs.

PMID:40365732 | DOI:10.1111/cns.70436