What if levetiracetam (Keppra) exacerbates aggression in patients?

Levetiracetam-Induced Aggression: Discontinue or Reduce Dose Immediately

If levetiracetam causes or worsens aggression, the medication should be discontinued or dose-reduced immediately, as this is a recognized adverse effect that can range from mild irritability to severe violence requiring psychiatric intervention. 1

Recognition and Incidence

Levetiracetam-induced aggression is a well-documented adverse effect that occurs more frequently than many clinicians realize:

• Aggression was specifically listed as a significant side effect in pediatric autism patients treated with levetiracetam 2
• The FDA label explicitly warns that non-psychotic behavioral disorders (including aggression and irritability) occurred in 5% of patients with myoclonic seizures on levetiracetam versus 0% on placebo 1
• In primary generalized tonic-clonic seizures, non-psychotic behavioral disorders (abnormal behavior, aggression, conduct disorder, irritability) occurred in 11.4% of levetiracetam patients versus 3.6% on placebo 1
• One study found aggressive episodes in 3.5% of levetiracetam-treated epilepsy patients compared to less than 1% not on levetiracetam 3

Severity Spectrum

The aggression can manifest across a wide spectrum:

• Mild to moderate cases (approximately 70% of affected patients): Transient irritability that may not require discontinuation 3
• Severe cases (approximately 30% of affected patients): Physical violence, psychiatric emergency requiring hospitalization, and in rare cases psychotic symptoms 3
• Extreme presentations: Seething rage, uncontrollable anger, fits of fury, suicidal tendencies, and violent attacks on family members 4

Immediate Management Algorithm

When aggression emerges or worsens on levetiracetam:

1. Discontinue levetiracetam immediately if aggression is severe (physical violence, suicidal ideation, psychotic features) 3, 4

   • Symptoms typically resolve within 24 hours of the last dose 5, 6
   • Do not rechallenge—reintroduction consistently causes recurrence 4

2. For moderate irritability, reduce the dose if seizure control permits 3

   • Approximately 10% of patients with mild symptoms required dose reduction 3
   • Monitor closely for escalation

3. Taper gradually if seizure risk allows to minimize withdrawal seizures, though behavioral urgency may necessitate rapid discontinuation 1

High-Risk Patient Identification

Screen carefully before initiating levetiracetam in patients with:

• Prior history of aggression or behavioral problems—these patients require particularly careful monitoring 3
• Pre-existing psychiatric disorders (schizoaffective disorder, mood disorders, psychosis)—significantly increased risk 7
• Autism spectrum disorder—aggression was a notable side effect in this population 2
• Pediatric and adolescent patients—behavioral abnormalities occurred in 37.6% versus 18.6% on placebo 1

Timeline and Monitoring

Behavioral symptoms typically emerge:

• Within the first week of initiation or dose increase 5, 4
• Can occur beyond the initial titration period and may be the most common reason for discontinuation 7
• Symptoms resolve rapidly (within 24 hours) after discontinuation 5, 6

Clinical Pitfalls to Avoid

• Do not attribute new aggression to the underlying seizure disorder or psychiatric comorbidity without considering levetiracetam as the cause—this delays appropriate intervention 7
• Do not attempt rechallenge in patients who developed severe aggression—case reports consistently show recurrence 4
• Do not underestimate the severity potential—while most cases are mild, severe violence requiring restraints and psychiatric hospitalization can occur 3, 6
• Do not assume tolerability based on initial weeks—behavioral effects can emerge later in treatment 7

Alternative Considerations

While levetiracetam is generally well-tolerated and effective, when behavioral side effects occur, alternative antiepileptic medications should be considered rather than persisting with dose adjustments in high-risk patients 5, 3