Tamiflu and Delusions: Evidence-Based Assessment
Direct Answer
Delusions have been reported in patients taking Tamiflu (oseltamivir), but multiple comprehensive reviews and controlled clinical trial data have failed to establish a causal link between the drug and neuropsychiatric events, including delusions. 1
Understanding the Evidence
Post-Marketing Reports vs. Controlled Studies
The evidence presents an important distinction between spontaneous reports and controlled trial data:
Transient neuropsychiatric events (including self-injury, delirium, abnormal behavior, hallucinations, and delusions) have been reported in post-marketing surveillance among persons taking oseltamivir, with the majority of reports coming from Japanese adolescents and adults. 1, 2
However, comprehensive reviews of controlled clinical trial data and ongoing surveillance have failed to establish a link between oseltamivir and neurologic or psychiatric events. 1
In phase III treatment studies, no difference in neuropsychiatric adverse event reporting rates was found between oseltamivir and placebo (0.5% vs 0.6%). 3
The Influenza Connection
A critical finding is that influenza infection itself is strongly associated with neuropsychiatric symptoms:
Analysis of the UK General Practice Research Database showed that the adjusted relative risk of neuropsychiatric events in influenza patients was 1.75 to 2.18-fold higher than in the general population, independent of oseltamivir exposure. 3, 4
Influenza can be associated with a variety of neurologic and behavioral symptoms including hallucinations, delirium, and abnormal behavior, sometimes resulting in fatal outcomes. 2
These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease. 2
Neuropsychiatric events in Japanese and Taiwanese children with influenza have occurred before the initiation of oseltamivir treatment, with events similar to those occurring after therapy initiation. 3
Epidemiological Evidence
A US healthcare claims database analysis of 159,386 oseltamivir-treated patients showed the risk of neuropsychiatric events was no higher than in 159,386 patients not receiving antivirals. 3
Between 1999 and 2007,3,051 spontaneous reports of neuropsychiatric events were received involving 2,466 patients who received oseltamivir out of approximately 48 million people treated worldwide (crude reporting rate of 99 per 1,000 prescriptions in children and 28 per 1,000 in adults in Japan). 3
Clinical Implications and Monitoring
FDA Guidance
The FDA advises that persons receiving oseltamivir be monitored closely for abnormal behavior. 1, 2
If neuropsychiatric symptoms occur, evaluate the risks and benefits of continuing oseltamivir for each patient. 2
Timing and Characteristics
When neuropsychiatric events are reported, they generally occur within 48 hours of the onset of influenza illness and initiation of treatment. 3, 4
The events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. 2
Mechanism Assessment
No mechanism by which oseltamivir or oseltamivir carboxylate could cause or worsen neuropsychiatric events has been identified. 3
Penetration into the CNS of both oseltamivir and its active metabolite is low (cerebrospinal fluid/plasma ratios of approximately 0.03). 3
Animal studies showed no specific CNS/behavioral effects after administration of doses corresponding to >100 times the clinical dose. 3
One animal study showed oseltamivir increased dopamine levels in the rat medial prefrontal cortex, which the authors suggested might relate to abnormal behaviors, though this has not been confirmed in humans. 5
Common Pitfalls to Avoid
Do not automatically attribute neuropsychiatric symptoms to oseltamivir without considering that influenza itself causes these symptoms at significantly elevated rates. 3, 4
Do not withhold oseltamivir from high-risk patients due to concerns about neuropsychiatric events, as the benefits of treatment (including mortality reduction) far outweigh the theoretical risks. 1
Do not ignore neuropsychiatric symptoms when they occur - monitor patients closely and evaluate whether continuation of therapy is appropriate based on individual risk-benefit assessment. 2
Bottom Line
While delusions and other neuropsychiatric events have been reported in patients taking Tamiflu, the preponderance of evidence from controlled trials, epidemiological studies, and mechanistic investigations indicates that these events are more likely attributable to influenza infection itself rather than the medication. 1, 3, 4 Close monitoring for abnormal behavior is advised, particularly in pediatric and adolescent patients, but this concern should not prevent appropriate use of oseltamivir in patients who would benefit from treatment. 2