Children who received oseltamivir during influenza infections experienced a reduced risk of serious neuropsychiatric events, including seizures and altered mental status, compared with those who did not, results from a large retrospective cohort study showed.1
“Most providers prescribe antivirals to reduce duration of symptoms,” said first author James Antoon, MD, PhD, MPH, of Monroe Carell Jr Children’s Hospital at Vanderbilt University, Nashville. “Our findings suggest that oseltamivir prevents influenza-associated neuropsychiatric events. Based on our study, providers and families should be reassured about the safety of oseltamivir. Providers can consider targeting their antiviral efforts to those at high risk for neurologic and psychiatric complications of influenza.”
For the trial published in JAMA Neurology, researchers looked back at medical records of 692,295 children aged 5 to 17 years who were enrolled in Tennessee Medicaid between July 1, 2016, and June 30, 2020. For each day of follow-up, the children were placed into one of five groups:
- Had influenza but did not receive treatment
- Had influenza and were treated
- Were in the recovery period after finishing oseltamivir
- Received oseltamivir to prevent influenza
- Had no influenza or treatment
The investigators used Poisson regression and other statistical methods to compare how often neuropsychiatric events occurred in each group, while considering other factors that could affect risk. The main outcome was a neuropsychiatric event that led to hospitalization.
The median age of the cohort was 11 years, and 50% were female. In all, the researchers determined that there were 1,230 serious neuropsychiatric events during 19,688,320 person-weeks of follow-up. Of these, 898 were neurologic and 332 were psychiatric, with the three most common being mood disorders (36.3%), self-harm behaviors (34.2%), and seizures (13.7%).
Among 151,401 influenza episodes, 66.7% (95% CI, 66.5%-67.0%) were treated with oseltamivir, including 60.1% (95% CI, 59.6%-60.6%) of individuals at high risk for influenza complications. Compared with untreated influenza, event rates were lower during oseltamivir-treated periods (IRR, 0.53; 95% CI, 0.33-0.88) and posttreatment periods (IRR, 0.42; 95% CI, 0.24-0.74). Subanalyses suggest that this reduction was primarily driven by a decrease in neurologic events (IRR, 0.45; 95% CI, 0.25-0.82) rather than psychiatric events (IRR, 0.80; 95% CI, 0.34-1.88). Sensitivity analyses suggest that misclassification or unmeasured confounding is unlikely to account for these findings.
“Our results demonstrate what many physicians have long suspected: that the flu, not the flu treatment, is associated with neuropsychiatric events,” Dr. Antoon said. “However, the finding that oseltamivir appears to lower the risk of neuropsychiatric events in children by about 50% was not expected. Yet, these findings are consistent with what we know about oseltamivir and reductions in other influenza-associated complications from randomized trials, such as [a] 33% reduction in ear infections and 50% reduction in pneumonia. Another interesting finding was the decrease in neuropsychiatric events was driven by neurologic events and less so by psychiatric events.”
While the study is the largest of its kind, he acknowledged certain limitations, including its retrospective cohort design and focus on Tennessee children with Medicaid. Randomized controlled trials on this topic are not feasible, he added, due to “the rarity of the neuropsychiatric events. It is also potentially unethical to randomize high-risk children to not receive a medication with known benefits. When data from [randomized controlled trials] are not available, rigorously performed cohort studies, such as this one, can inform the risk-benefit profile of medications.”
Lina Miyakawa, MD, FCCP, Medical Director of Critical Care and Vice-Chair of Quality, Department of Medicine, for Newark Beth Israel Medical Center, who was not affiliated with the study, said the work represents a timely clarification of oseltamivir’s safety as the flu season progresses.
“This counters many years of uncertainty, fueled by anecdotal reports,” she said. “Its findings help shift the narrative from concern about the drug’s neurotoxicity to recognition that influenza itself drives neuropsychiatric complications and may strengthen confidence in antiviral treatment as both safe and beneficial, or even so far to say, protective.”
She recommended that future studies assess “mild” or outpatient neuropsychiatric events, account for viral strain and vaccination status, and confirm these findings in diverse populations to ensure generalizability.
“Mechanistic studies could also provide further clarification on how the therapy mitigates neurologic injury,” Dr. Miyakawa said.
References
1. Antoon JW, Williams DJ, Bruce J, Sekmen M, Zhu Y, Grijalva CG. Influenza with and without oseltamivir treatment and neuropsychiatric events among children and adolescents. JAMA Neurol. 2025;82(10):1013-1021. doi:10.1001/jamaneurol.2025.1995
