Hyponatremia risk varies among individual second-generation antipsychotic drugs

Antipsychotics are used to treat schizophrenia, along with bipolar disorder and major depressive disorder. However, these medications can be associated with hyponatremia, a serious reduction in blood sodium levels. Although second-generation antipsychotics have been suggested to be associated with a lower risk of hyponatremia than first-generation antipsychotics, it remains unclear whether this risk differs between individual second-generation medications.

Addressing this challenge, a research team led by Associate Professor Masakazu Hatano from the Department of Pharmacotherapeutics and Informatics, Fujita Health University School of Medicine, Japan, along with Dr. Takenao Koseki, Dr. Takeo Saito, and Dr. Shigeki Yamada, all affiliated with the same institution, compared the risk of hyponatremia associated with individual second-generation antipsychotics. The study was published online on August 13, 2026, in Volume 9, Issue 8, of the journal JAMA Network Open.

"Hyponatremia is a safety concern associated with antipsychotic use, but comparative evidence among individual second-generation antipsychotics remains limited," says Dr. Hatano. "We therefore adopted a two-stage approach. First, we used a spontaneous reporting system to generate hypotheses regarding hyponatremia risk among individual second-generation antipsychotics; second, we used a claims database to evaluate the associations obtained from the spontaneous reporting system."

The researchers first examined reports from the US Food and Drug Administration Adverse Event Reporting System from quarter 4 of 1997 to quarter 3 of 2023, then subsequently evaluated the associations in a Japanese hospital-based claims database covering April 2008 to April 2024.

The US safety reporting analysis included 17,805,418 reports, of which 458,745 involved second-generation antipsychotic monotherapy. Several antipsychotics showed lower reporting odds for hyponatremia than olanzapine, the reference antipsychotic. Brexpiprazole and lurasidone showed the lowest reporting odds relative to olanzapine. However, these findings were hypothesis-generating because spontaneous reporting data do not provide denominator information and cannot measure actual incidence or absolute risk.

The researchers then evaluated the hypotheses using the Japanese hospital-based claims database. 55,394 patients prescribed with antipsychotics were included in the final analysis and had no recent antipsychotic use or hyponatremia, and were followed for up to 180 days after treatment initiation. During follow-up, hyponatremia occurred in 366 patients (0.7%) of the cohort.

After accounting for differences in baseline characteristics and other factors influencing risk, aripiprazole was associated with a significantly lower risk of hyponatremia than olanzapine. Other antipsychotics did not show significant differences compared with olanzapine after adjustment.

"These findings suggest that the risk of hyponatremia may differ among individual second-generation antipsychotics," clarifies Dr. Hatano. "Aripiprazole was associated with a lower risk than olanzapine in our adjusted analysis, which may help inform antipsychotic selection for patients at higher risk of hyponatremia."

However, researchers emphasized that the study was observational, so residual confounding and differences in how hyponatremia was detected may have influenced the findings.

Overall, the study provides evidence that hyponatremia risk may not be identical across second-generation antipsychotics. By combining evidence from a pharmacovigilance database with claims data, the research provides complementary evidence for comparing drug safety while recognizing important limitations. The findings will guide treatment decisions for patients at higher risk of hyponatremia. Further studies are needed to elucidate the associations between individual second-generation antipsychotics and hyponatremia.