Keppra (Levetiracetam) and Suicidal Ideation
Risk Profile
Levetiracetam carries an FDA black box warning for increased risk of suicidal thoughts and behavior, with approximately twice the risk compared to placebo (adjusted relative risk 1.8), representing one additional case of suicidal thinking or behavior for every 530 patients treated. 1
Quantified Risk Data
- Incidence in epilepsy trials: 0.43% in levetiracetam-treated patients versus 0.24% in placebo patients 1
- Time to onset: Risk emerges as early as one week after starting treatment and persists throughout therapy 1
- Reported incidence: 0.5-0.7% of patients develop suicidal ideation during levetiracetam treatment 2
High-Risk Patient Subgroups
Specific populations require heightened vigilance when prescribed levetiracetam 3:
- Prior psychiatric disorder (especially depression or bipolar disorder)
- History of traumatic brain injury
- History of substance use disorder
- Structural brain abnormalities
These patients constitute a vulnerable subgroup with substantially elevated risk and mandate close monitoring 3.
Clinical Management Algorithm
Before Initiating Levetiracetam
Screen for suicide risk factors including self-directed violence history, current psychiatric conditions, psychiatric symptoms, social determinants of health, adverse life events, access to lethal means, physical conditions, and demographic characteristics 4.
Use validated screening tools 4:
- Columbia Suicide Severity Rating Scale Screener (general population)
- Patient Health Questionnaire-9 (general population)
- Beck Suicide Intent Scale/Beck Scale for Suicidal Ideation (high-risk populations)
Patient and Family Education
Inform patients, caregivers, and families that levetiracetam increases the risk of suicidal thoughts and behavior 1. They must be alert for:
- Emergence or worsening of depression
- Unusual changes in mood or behavior
- Suicidal thoughts, behavior, or thoughts about self-harm
- These symptoms should be reported immediately to healthcare providers 1
Monitoring During Treatment
Schedule closely-spaced follow-up appointments (at least weekly initially) with systematic assessment for suicidal ideation at every visit, particularly during dose adjustments 5, 6.
Monitor for neuropsychiatric adverse events that commonly occur within the first 4 weeks 1:
- Somnolence (14.8% vs 8.4% placebo)
- Asthenia/fatigue (14.7% vs 9.1% placebo)
- Coordination difficulties (3.4% vs 1.6% placebo)
- Behavioral abnormalities (5% of patients discontinued due to psychiatric symptoms) 1
Implement third-party medication monitoring where a responsible family member controls and dispenses medications, reporting behavioral changes, increased agitation, or side effects immediately 7, 5.
If Suicidal Ideation Emerges
Do not automatically discontinue levetiracetam - balance the risk of suicidal thoughts against the risk of uncontrolled seizures, which can result in serious harm including death 3, 8.
Determine if symptoms are medication-related or illness-related 1. Research suggests levetiracetam-induced suicidality correlates with depression and hopelessness rather than anxiety or impulsiveness 2.
Initiate cognitive behavioral therapy focused on suicide prevention immediately - this reduces suicidal ideation and cuts suicide attempt risk by half compared to treatment as usual 4, 7, 5.
Consider psychiatric consultation for patients with multiple risk factors, particularly those with severe psychiatric illness history 3.
If suicidal ideation is clearly medication-related and severe, discontinuation typically results in symptom resolution within 5 days 2.
Safety Interventions for Active Suicidal Ideation
Hospitalization is indicated for patients with active suicidal ideation, worsening depression, and functional decline 7, 6.
Remove access to lethal means including all medications from the home, with explicit instructions about firearm removal and securing potentially lethal substances 7, 6.
Develop a collaborative crisis response plan identifying warning signs, coping skills, social support contacts, and crisis resources 4, 5.
Avoid "no-suicide contracts" as they have no empirical evidence supporting efficacy and create false reassurance 7, 5, 6.
Critical Pitfalls to Avoid
Never withhold or stop levetiracetam solely based on suicidal risk without considering the potentially fatal consequences of uncontrolled seizures 3, 8. The risk of stopping antiepileptic drugs is significantly worse than the suicidal risk itself 8.
Do not rely exclusively on screening tools for risk stratification - use multiple assessment methods including clinical interviews 4.
Do not assume patients who deny suicidal ideation are safe - maintain clinical vigilance and environmental safety measures regardless of verbal agreements 7, 5.
Do not prescribe medications with high lethality in overdose (such as tricyclic antidepressants) to patients on levetiracetam with any suicidal risk 5.
Mechanism and Time Course
The mechanism by which levetiracetam induces suicidality appears related to depression and hopelessness rather than anxiety or impulsiveness 2. When suicidal ideation develops, it typically resolves within 5 days of discontinuation if clearly medication-related 2.