Avian Flu Diary: JAMA Neuro: Influenza With and Without Oseltamivir Treatment and Neuropsychiatric Events Among Children and Adolescents

#18,836

For twenty years the influenza antiviral Tamiflu (oseltamivir) has carried a `black box warning' regarding potential neuropsychiatric events in children and adolescents; including confusion, delirium, abnormal behavior, self-harm, and even suicidal behavior.

These warnings were largely based on anecdotal reports from Japan in the mid-2000s - which were widely repeated by the tabloid press, and amplified online - and not based on real studies.

While a lot of people remember (and continue to repeat) those press reports, few bother to cite the 2008 study which found no link between the drug and those events (see Japan: No Link Between Tamiflu And Abnormal Behavior).

Or the 2010 a review in the journal Eurosurveillance: Adverse Effects of Oseltamivir in Children which, looked at the antiviral treatment of a number of students at a primary school in Sheffield, UK during the 2009 pandemic which found none of the side effects reported were life-threatening.

Again in 2012, in Study: Adverse Events Associated With Oseltamivir Outpatient Treatment, researchers writing in the journal Pharmacoepidemiology and Drug Safety, found `no evidence was identified for an increased risk of neuropsychiatric or other AEs following oseltamivir treatment.’

Still, social media rumors and press reports have continued to cast doubt on the drug's safety - particularly when administered to children and adolescents.

In 2018, we revisited this story (see Study Finds No Relationship Between Suicide & Oseltamivir In Pediatric Patients), where a study published in the Annals of Family Medicine, once again found no credible link between the use of oseltamivir and neuropsychiatric events in pediatric patients.

What was becoming increasingly apparent, however, was that influenza itself (both seasonal and novel) could produce significant neurological manifestations, particularly in children and adolescents.

In 2018's Neuroinfluenza: A Review Of Recently Published Studies, we looked at a CDC COCA Call - and a number of recent studies - illustrating the threat.

Since then Neuroinfluenza has gotten a great deal more attention, but the stigma attached to oseltamivir has remained.

Today we've yet another study, published in JAMA, which finds the exact opposite; that oseltamivir reduces the risk of serious neuropsychiatric events in children and adolescents with influenza.

I've only posted the abstract - along with a link to a press release - so follow the link(s) to read it in its entirety. I'll have a bit more after the break.

Influenza With and Without Oseltamivir Treatment and Neuropsychiatric Events Among Children and Adolescents

James W. Antoon, MD, PhD, MPH1; Derek J. Williams, MD, MPH1; Jean Bruce, BS2; et al

Published Online: August 4, 2025
doi: 10.1001/jamaneurol.2025.1995

Key Points

Question Is the use of the influenza antiviral oseltamivir associated with serious neuropsychiatric events?

Findings In this cohort study, the risk of serious neuropsychiatric events was lowest during periods without influenza. During influenza periods, treatment with oseltamivir was associated with a reduced risk of serious neuropsychiatric events compared with influenza periods without oseltamivir treatment.

Meaning Oseltamivir use was associated with a reduced risk of serious neuropsychiatric events when used for influenza treatment; findings from this study should inform both caregivers and clinicians on the safety of oseltamivir and its role in preventing influenza-associated complications.

Abstract

Importance Reports of pediatric neuropsychiatric events during influenza treatment with oseltamivir have prompted public concerns. However, whether oseltamivir or influenza infection is associated with increased risk of neuropsychiatric events remains unclear.

Objective To determine the association between influenza, oseltamivir, and serious neuropsychiatric events.

Design, Setting, and Participants This retrospective cohort study was conducted in a population-based ambulatory setting during the 2016 to 2017 and 2019 to 2020 influenza seasons. Follow-up began on the first day of the influenza season and continued through the earliest occurrence of an outcome event, loss of enrollment, death, age 18 years, or end of the season or study. Children aged 5 to 17 years enrolled in Tennessee Medicaid were for eligible for inclusion. Data analysis was completed from July 2023 to March 2025.

Exposures Each person-day of follow-up was assigned to 1 of the following 5 mutually exclusive exposure groups: (1) untreated influenza; (2) treated influenza; (3) posttreatment period (period between oseltamivir completion and end of influenza period); (4) influenza prophylaxis; and (5) no exposure.

Main Outcomes and Measures The primary outcome was a neuropsychiatric event requiring hospitalization, and events were identified using a validated algorithm. Poisson regression estimated incidence rate ratios (IRRs) while accounting for relevant covariates measured on each person-day. Sensitivity analyses examined robustness of findings to alternate exposure and outcome definitions, time-varying outcome risk, negative control outcome, and unmeasured confounding.

Results Among 692 975 eligible children, a total of 692 295 children (median [IQR] age, 11 [7-14] years; 50.3% female) experienced 1230 serious neuropsychiatric events (898 neurologic and 332 psychiatric) during 19 688 320 person-weeks of follow-up. Among the 151 401 influenza episodes, 66.7% (95% CI, 66.5%-67.0%) were dispensed oseltamivir (60.1% [95% CI, 59.6%-60.6%] among those at high risk for influenza complications). The most common events overall were mood disorders (36.3%) and suicidal or self-harm behaviors (34.2%).

Compared with untreated influenza, event rates were lower during oseltamivir-treated influenza 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 finding is driven more by a reduction in neurologic events (IRR, 0.45; 95% CI, 0.25-0.82) than psychiatric events (IRR, 0.80; 95% CI, 0.34-1.88). Sensitivity analyses suggest misclassification or unmeasured confounding would not explain these findings.

Conclusions and Relevance In this cohort study, oseltamivir treatment during influenza episodes was associated with a reduced risk of serious neuropsychiatric events. These findings support oseltamivir use for prevention of these influenza-related complications.

A press release from Vanderbilt University Medical Center on this study can be read at:

Researchers debunk long-standing concern about flu treatment in children

Admittedly, this is an observational study - albeit a fairly large one - and not a randomized control trial. While RCTs in children might better confirm these findings, withholding treatment from infected cohorts presents obvious ethical problems.

None of this is to suggest that oseltamivir is 100% benign in 100% of patients, but side effects are generally mild, with nausea and vomiting being the most commonly reported.

Whether this study will change many minds remains to be seen. Negative views, once baked into the social consciousness, are notoriously difficult to change.