Aripiprazole Linked to Lower Hyponatremia Risk Than Olanzapine, suggests study

A large retrospective cohort study published in The Journal of the American Medical Association found that aripiprazole was associated with a lower risk of hyponatremia when compared to olanzapine in antipsychotic users. Although residual confounding cannot be excluded, the findings may help guide antipsychotic selection, particularly in patients at high risk for hyponatremia.

Hyponatremia is a recognized adverse effect of antipsychotic therapy and can lead to symptoms ranging from fatigue and confusion to seizures and life-threatening neurological complications in severe cases. While previous research has linked antipsychotics to this condition, comparative evidence between individual second-generation antipsychotics has remained limited.

Thus, this retrospective cohort study along with a disproportionality analysis using data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) and a large Japanese hospital-based claims database was conducted. The analysis covered data spanning over two decades and included patients aged 18 to 69 years who were newly prescribed second-generation antipsychotics, with no prior history of antipsychotic use or hyponatremia during the 6 months preceding treatment initiation.

Out of more than 961,000 patients prescribed antipsychotics in the Japanese database, 55,394 met the strict eligibility criteria of the study. The average participant age was 50.4 years, with women accounting for 53.4% of the study population. This research tracked the incidence of hyponatremia within 180 days after treatment initiation while adjusting for potential confounding factors using propensity score weighting.

The results showed that aripiprazole users had a 48% lower risk of developing hyponatremia when compared to patients receiving olanzapine, with an adjusted hazard ratio of 0.52 (95% confidence interval, 0.35–0.76). Other second-generation antipsychotics did not demonstrate statistically significant differences in risk relative to olanzapine. Findings from the FAERS database also indicated that several antipsychotics had lower reporting odds ratios for hyponatremia than olanzapine, supporting the overall trend observed in the claims analysis.

Overall, the findings suggest that for patients who are already at elevated risk of hyponatremia the choice of antipsychotic may influence safety outcomes. While further research is warranted to confirm these observations, the study provides new comparative evidence suggesting that aripiprazole may be a safer option than olanzapine with respect to hyponatremia risk, helping clinicians make more informed treatment decisions.

Source:

Hatano, M., Koseki, T., Saito, T., & Yamada, S. (2026). Comparative risk of hyponatremia among patients treated with second-generation antipsychotics. JAMA Network Open, 9(8), e2628796. https://doi.org/10.1001/jamanetworkopen.2026.28796