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.
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Reference
Title of original paper: Comparative Risk of Hyponatremia Among Patients Treated With Second-Generation Antipsychotics
Journal: JAMA Network Open
DOI: https://doi.org/10.1001/jamanetworkopen.2026.28796
About Fujita Health University
Fujita Health University (FHU) is a private medical university located in Aichi, Japan. Established in 1964, it houses one of the largest university hospitals in Japan. It's 900 member faculty provides diverse learning and research opportunities to medical students worldwide. Guided by its founding philosophy of "Our creativity for the people" Fujita Health University believes that it's students can shape the future through creativity and innovation. FHU has earned global recognition, ranking eighth among all universities and second among private universities in Japan in the 2020 Times Higher Education (THE) World University Rankings. The university ranked fourth worldwide in the 2024 THE University Impact Rankings for contributions to the "Good Health and Well-being" SDG (Sustainable Development Goals) of the United Nations (UN). In June 2021, the university made history as the first Japanese institution to host the THE Asia Universities Summit. In 2024, Fujita Health University was awarded the Forming Japan’s Peak Research Universities (J-PEAKS) Program by the Japanese government to establish an innovative academic drug discovery ecosystem and hub of a multi-university consortium for research and education.
Website: https://www.fujita-hu.ac.jp/
About Associate Professor Masakazu Hatano from Fujita Health University
Dr. Masakazu Hatano is an Associate Professor in the Department of Pharmacotherapeutics and Informatics, Fujita Health University School of Medicine, Japan. His research focuses on psychopharmacology, psychiatry, pharmacoepidemiology, and pharmacovigilance. His academic work includes studies using large healthcare databases and spontaneous reporting systems to evaluate clinical pharmacotherapy and treatments for mental disorders. Through studies using data and safety reporting systems, he contributes to understanding medication-related risks and supporting evidence-based decisions in psychiatric care and pharmacotherapy.
Funding information
This study was supported by The Research Foundation for Pharmaceutical Sciences (JSPS KAKENHI grant 26K18918).
JAMA Network Open
10.1001/jamanetworkopen.2026.28796
Observational study
People
Comparative Risk of Hyponatremia Among Patients Treated With Second-Generation Antipsychotics
13-Aug-2026
Dr Hatano reported receiving personal fees from Meiji Seika Pharma and Taisho Pharmaceutical during the conduct of the study. Dr Koseki reported receiving personal fees from Merck Biopharma outside the submitted work. Dr Saito reported receiving personal fees from Otsuka Pharmaceutical and Sumitomo Pharma during the conduct of the study. Dr Yamada reported receiving personal fees from Asahi Kasei Corporation, AstraZeneca KK, Daiichi Sankyo, EA Pharma, Eisai, Fuji Pharma, Kyowa Kirin, Meiji Seika Pharma, Nippon Shinyaku, Nipro Corporation, Ono Pharmaceutical, Otsuka Pharmaceutical Factory, Pfizer Japan, Taisho Pharmaceutical, Takeda Pharmaceutical, Toa Eiyo, Towa Pharmaceutical, and Yakult Honsha; and receiving grants from EA Pharma, Kissei Pharmaceutical, Mochida Pharmaceutical, Otsuka Pharmaceutical Factory, and SUGI Holdings during the conduct of the study. No other disclosures were reported.