Comparative Risk of Hyponatremia Among Patients Treated With Second-Generation Antipsychotics
Masakazu Hatano, Takenao Koseki, Takeo Saito, Shigeki YamadaImportance
Hyponatremia is an adverse event associated with antipsychotic use; however, comparative evidence among individual second-generation antipsychotics remains limited.
Objective
To compare the risk of hyponatremia associated with individual second-generation antipsychotics.
Design, Setting, and Participants
In this retrospective cohort study and disproportionality analysis, data were obtained from the US Food and Drug Administration Adverse Event Reporting System (FAERS; quarter 4 1997 to quarter 3 2023), a dataset provided by the Japan Pharmaceutical Information Center, and a Japanese hospital-based claims database (Medical Data Vision; April 2008 to April 2024). The study adopted a new-user design and included patients routinely prescribed antipsychotics. Patients aged 18 to 69 years with at least 180 days of active medical history preceding the initial antipsychotic prescription, with no history of antipsychotics or hyponatremia during that period, were included.
Exposures
Initiation of second-generation antipsychotics.
Main Outcomes and Measures
Hyponatremia associated with individual antipsychotics was compared with that associated with olanzapine. Reporting odds ratios with 95% CIs were calculated for FAERS. The incidence within 180 days of treatment initiation was analyzed for claims database using hazard ratios estimated with stabilized inverse probability of treatment weighting based on propensity scores.
Results
In the FAERS database, most antipsychotics showed lower reporting odds ratios for hyponatremia than olanzapine. In a Japanese claims database, among 961 010 patients prescribed antipsychotics, 55 394 were included in the final analysis. The mean (SD) age was 50.4 (14.3) years, and there were 25 839 (46.6%) male and 29 555 (53.4%) female patients. After stabilized inverse probability of treatment weighting, aripiprazole was associated with a significantly lower risk of hyponatremia than olanzapine (adjusted hazard ratio, 0.52; 95% CI, 0.35-0.76), whereas other antipsychotics showed no significant differences. Sensitivity analysis confirmed the robustness of the findings.
Conclusions and Relevance
In this retrospective cohort study of antipsychotic users, aripiprazole was associated with a lower risk of hyponatremia than was olanzapine. Although residual confounding should be considered, these findings may help inform clinical decision-making for high-risk patients.