Keppra and Neuropsychiatric Adverse Effects
Yes, Keppra (levetiracetam) can cause both agitation and suicidal ideation, and these risks are explicitly documented in the FDA-mandated boxed warning for all antiepileptic drugs. 1
FDA Boxed Warning on Suicidal Ideation
All antiepileptic drugs (AEDs), including levetiracetam, carry an FDA boxed warning for increased risk of suicidal thoughts or behavior in patients taking these medications for any indication. 1
Pooled analyses of 199 placebo-controlled clinical trials demonstrated that patients on AEDs had approximately twice the risk (adjusted Relative Risk 1.8) of suicidal thinking or behavior compared to placebo-treated patients. 1
The estimated incidence rate of suicidal behavior or ideation among AED-treated patients was 0.43%, compared to 0.24% among placebo-treated patients, representing an increase of approximately one case for every 530 patients treated. 1
This increased risk was observed as early as one week after starting treatment and persisted for the duration of treatment assessed. 1
The FDA mandates close monitoring for suicidality, especially in the first months of treatment and following dosage adjustments. 1
Agitation and Behavioral Adverse Effects
Levetiracetam is well-documented to cause behavioral changes including aggression, agitation, anger, anxiety, hostility, and irritability. 1
In controlled clinical trials of adult patients with partial onset seizures, agitation occurred in 6% of levetiracetam-treated patients versus 1% of placebo patients, and hostility occurred in 2% versus <1%. 1
In pediatric patients, agitation occurred in 6% of levetiracetam-treated patients versus 1% of placebo patients, and personality disorder occurred in 8% versus 7%. 1
Behavioral activation/agitation (including motor or mental restlessness, insomnia, impulsiveness, disinhibited behavior, and aggression) may occur early in treatment, with dose increases, or with concomitant administration of drugs that inhibit levetiracetam metabolism. 2
High-Risk Patient Populations
Patients with prior psychiatric disorders, history of traumatic brain injury, history of substance use disorder, or structural brain abnormalities constitute a specific subgroup with increased vulnerability to suicidal ideation or behavior when prescribed levetiracetam. 3
Case reports and case series have documented severe manifestations including "levetiracetam-induced rage" characterized by seething rage, uncontrollable anger, fits of fury, depression, violence, and suicidal tendencies. 4
These severe behavioral reactions can occur within the first week of initiating levetiracetam and may resolve rapidly upon discontinuation, only to reappear with reintroduction. 4, 5
Clinical Monitoring Recommendations
Patients, caregivers, and families must be counseled about the risk of behavioral changes and suicidal thoughts before starting levetiracetam, and should be instructed to report any unusual changes in mood or behavior immediately. 1
Close monitoring is essential during the initial treatment period, after dose increases, and in patients with pre-existing psychiatric conditions or other identified risk factors. 3, 6
Neuropsychiatric evaluation for prior mood or psychiatric disorders should be performed before initiating levetiracetam therapy. 4
The risk of suicidality must be balanced against the risk of untreated seizures, as uncontrolled epilepsy itself carries significant morbidity and mortality risks. 1, 3
Management of Adverse Effects
If severe behavioral changes, aggression, or suicidal ideation develop, levetiracetam should be discontinued promptly, as symptoms typically resolve rapidly after cessation. 4, 7, 5
Psychiatric consultation is invaluable in the care of patients with multiple risk factors for neuropsychiatric adverse effects. 3
In cases of mild behavioral symptoms, dose reduction may be sufficient to manage adverse effects while maintaining seizure control. 6