Not a drug side effect, but the flu itself: a large study has rehabilitated oseltamivir in children

For two decades, there has been a debate over whether the antiviral drug oseltamivir (Tamiflu) triggers “neuropsychiatric events” in children, ranging from confusion to hallucinations, or whether the flu virus itself is to blame. A large-scale study from Vanderbilt has found an answer: in children with the flu, treatment with oseltamivir is associated with a ~50% lower risk of serious neuropsychiatric events, while in children who took the drug prophylactically without the flu, the risk is no higher than baseline. In other words, the flu, not Tamiflu, is causing the risk. The study is published in JAMA Neurology.

Background of the study

Ever since the "bird" and seasonal outbreaks of the 2000s, pediatricians have had an alarming question: why do some children develop seizures, confusion, psychotic episodes, and abrupt behavioral changes against the background of the flu - from the virus or from the treatment? The flu itself can affect the nervous system (febrile seizures, encephalopathy, post-infectious psychiatric phenomena), and the risk is higher with high fever, dehydration, and an inflammatory cascade. Against this background, cases of neuropsychiatric events in children receiving oseltamivir entered the public arena, and the drug acquired a reputation as potentially "dangerous for the brain."

Pharmacologically, oseltamivir has no obvious “neuropsychiatric” targets: it is a prodrug that blocks viral neuraminidase, with limited penetration through the blood-brain barrier at standard doses. But clinical epidemiology knows the effect of “mixed indications”: more severe patients are often treated more actively, which means their initial risk of complications is higher regardless of therapy. Hence the dilemma: if a child on the 2nd or 3rd day of influenza develops seizures or hallucinations while taking Tamiflu, this does not prove causality - the disease and its inflammatory background themselves could have triggered the event.

To cut the knot, we need large, well-designed cohorts with precise “time-matching”: compare children in periods with and without confirmed influenza; among those who got sick, compare those who received oseltamivir with those who did not; look separately at prophylactic courses in contacts without infection. Hard endpoints (hospitalizations/emergency visits due to seizures, encephalitis, psychosis, suicidal behavior) are also important, as are methods that minimize systematic errors (self-monitoring within one patient, taking into account comorbidity, age, season).

Pediatric practice is in dire need of such an answer: parents and some doctors sometimes postpone therapy because of old "horror stories", although it is the early suppression of viral replication that potentially reduces the risk of complications - including neurological ones. If it is proven that the main contribution to neuropsychiatric events in children is made by the flu itself, and antiviral therapy does not increase, but reduces this risk, this will strengthen recommendations for early administration and help remove the stigma around the drug.

What exactly was shown

• Influenza itself increases the risk of neuro- and psychiatric complications in children compared with children who have not had influenza.
• Among people with influenza, treatment with oseltamivir reduced the risk of serious neuropsychiatric events by approximately half compared with no treatment.
• Prophylactic administration of oseltamivir to children without influenza did not increase risk compared with baseline.

How the study was conducted

The retrospective cohort study included 692,295 children and adolescents aged 5-17 years insured in the Tennessee Medicaid system (observation: 2016-2020). During the observation period, 1,230 serious neuropsychiatric events were recorded (898 neurological and 332 psychiatric). “Serious” events included, for example, seizures, encephalitis, disturbances of consciousness, movement disorders, as well as suicidal or self-harming behavior, psychosis/hallucinations, severe mood disorders.

• Authors' design and conclusions (PubMed abstract): During influenza periods, oseltamivir is associated with a reduced risk of serious neuropsychiatric events; results support the use of the drug for the prevention of influenza complications.

Why it matters - and what will change in practice

• Relieving a long-standing fear. For years, Tamiflu packaging carried a "black border" warning about possible neuropsychiatric effects. New evidence suggests that the flu, not the drug, is to blame, and that the therapy actually protects.
• Do not delay treatment. If influenza is suspected in a child (especially from risk groups), early initiation of oseltamivir may reduce the risk of neurological/psychiatric complications.
• Compliance with recommendations. The authors emphasize: this strengthens the position of professional communities (including the AAP) on the prescription of antivirals for influenza in children.

Facts and figures worth remembering

• 692,295 children aged 5-17 years; 4 years of observation (2016-2020).
• 1,230 serious neuropsychiatric events during the period (≈900 neurological and 330 psychiatric).
• In patients with influenza, oseltamivir reduces the risk of such events by ~50% compared to no therapy.

Context of the 2024/25 season

Many centers have reported more frequent and severe neurologic complications of influenza in children this past season (including seizures and necrotizing encephalopathy) - another argument not to delay antiviral therapy when clinically suspected.

Nuances and limitations

• Observational design: ideal is RCT, but here they used large real-world data; residual confounding is possible.
• Generalizability: cohorts - Tennessee Medicaid; results need to be confirmed in other states/countries and insurance populations.
• Rare events ≠ zero risk: As with any drug, individual reactions are possible; monitoring for symptoms is essential. (But new data suggest that on average the balance is clearly in favor of treatment.)

What should parents do?

• Contact your pediatrician at the first sign of flu symptoms - best started within the first 48 hours.
• Don't stop treatment because of Tamiflu 'horror stories': evidence shows protective effect on the nervous system.
• Monitor your child's condition as with any illness/medication (drowsiness, seizures, behavior) - if you are worried, seek help.

Authors' comment

The authors state their conclusion quite bluntly: the source of risk is influenza itself, not oseltamivir. In their cohort of children with laboratory/clinical confirmation of influenza, oseltamivir was associated with an approximately 50% lower risk of serious neuropsychiatric events, whereas prophylactic use without influenza did not increase the risk relative to baseline. These results, the team says, support the use of oseltamivir to prevent influenza complications in pediatric patients.

What the authors emphasize separately:

• Three observations taken together do not support the hypothesis of “provocation” of events by the drug itself: (1) periods of influenza are associated with an increase in risk; (2) during influenza, treatment is associated with a decrease in risk; (3) without influenza, prophylactic oseltamivir does not increase risk.
• Practical meaning: if there is a clinical suspicion of influenza in a child, do not delay therapy, especially in risk groups; concerns about “neuropsychiatric side effects” should not interfere with timely administration.
• Design limitations: This is an observational study, albeit on a very large base (≈692,000 children; 1,230 serious events). Residual confounding is possible, so the authors call for replication in other populations. Rare individual reactions cannot be ruled out - clinical observation remains mandatory.

The group's final position: "Our data are consistent with influenza increasing the risk of serious neuropsychiatric events and oseltamivir protecting against them" - and this should guide both physicians and parents in making decisions during flu season.

Conclusion

Big data from the "real world" has dispelled an old myth: oseltamivir does not provoke neuropsychiatric events in children - on the contrary, in case of flu it reduces their risk by about half. This means that the key danger comes from the virus itself, and timely antiviral therapy is one of the working ways to reduce this danger.

Source (original study): Influenza With and Without Oseltamivir Treatment and Neuropsychiatric Events Among Children and Adolescents, JAMA Neurology, 2025. doi: 10.1001/jamaneurol.2025.1995