Can Levetiracetam Cause Psychosis?
Yes, levetiracetam (Keppra) can definitively cause psychosis, and this is a well-documented adverse effect recognized in the FDA drug label. This is a serious neuropsychiatric complication that requires immediate recognition and management.
Evidence from FDA Drug Label
The FDA label for Keppra explicitly documents psychotic symptoms as an adverse effect 1. In controlled trials of adults with partial onset seizures:
- 0.7% of levetiracetam-treated patients experienced psychotic symptoms compared to 0.2% of placebo patients
- Two patients (0.3%) were hospitalized and required treatment discontinuation
- Psychosis typically developed within the first week of treatment and resolved within 1-2 weeks after discontinuation
- Some patients experienced hallucinations that occurred after 1-5 months of treatment
- One case of psychotic depression resolved within 45 days while continuing treatment
In pediatric patients, 3.0% discontinued treatment due to psychotic and nonpsychotic adverse events 1.
Clinical Manifestations
The psychotic symptoms associated with levetiracetam include 1:
- Delusions (most common manifestation)
- Auditory hallucinations
- Aggressive behavior
- Agitation
- Suicidal thoughts (in severe cases)
Recent research confirms these findings, with a 2024 study showing that among 1,412 patients taking levetiracetam, 7.8% exhibited severe psychiatric symptoms, with hallucinations, delusions, aggressive behavior, and agitation being the most common 2.
Time Course and Risk Factors
Most psychotic episodes occur within the first 4 weeks of treatment, particularly in the first week 1. However, onset can be delayed by several months in some cases.
Contributing factors that increase risk include 3, 4:
- History of psychiatric illness
- Developmental delay
- Underlying structural brain abnormalities (including temporal lobe epilepsy)
- Uncontrolled seizures (present in 66% of cases in one systematic review) 5
- Rapid dose escalation or high initial doses without gradual uptitration 4
Management Algorithm
When psychosis develops on levetiracetam:
Immediately reduce the dose or discontinue levetiracetam - symptoms typically resolve within 1-2 weeks of discontinuation 1
Add antipsychotic medication if symptoms are severe while tapering levetiracetam 2
Consider hospitalization if patient poses safety risk to self or others (as occurred in 0.3% of trial patients) 1
Switch to alternative antiepileptic drug - the ESETT trial demonstrated that fosphenytoin and valproate are equally effective alternatives 6
Critical Clinical Pitfall
Do not attribute new-onset psychosis solely to the underlying epilepsy without considering levetiracetam as the cause. While the 2024 ACR guidelines note that secondary psychosis can result from neurologic disorders and drug-related side effects 7, the temporal relationship (onset within days to weeks of starting levetiracetam) and rapid resolution upon discontinuation strongly support drug causality in most cases 8.
A 2026 systematic review attempted to downplay causality, suggesting alternative explanations 5. However, this contradicts the FDA label data from controlled trials showing clear excess risk compared to placebo, and multiple case reports demonstrating complete resolution within days of stopping the medication 8, 4.
Monitoring Recommendations
All patients starting levetiracetam must be counseled about psychiatric adverse effects 1. Patients, caregivers, and families should be instructed to immediately report:
- Emergence of hallucinations or delusions
- Unusual changes in mood or behavior
- Aggressive or hostile behavior
- Suicidal thoughts
Vigilant monitoring during the first month of treatment is essential, as this is when most cases occur 3, 2.