Can Keppra (levetiracetam) be used for mood disorders?

Keppra (Levetiracetam) Should NOT Be Used as a Primary Treatment for Mood Disorders

Levetiracetam is FDA-approved exclusively for seizure disorders, not mood disorders, and lacks guideline support or high-quality evidence for use in bipolar disorder or depression. 1

Why Levetiracetam Is Not Recommended for Mood Disorders

Lack of Guideline Support and FDA Approval

• The American College of Physicians guidelines for treating depressive disorders recommend second-generation antidepressants (SSRIs, SNRIs) as first-line pharmacotherapy, with no mention of levetiracetam. 2
• The American Academy of Child and Adolescent Psychiatry recommends lithium, valproate, or atypical antipsychotics for bipolar disorder treatment, not levetiracetam. 3
• Levetiracetam's FDA labeling is limited to partial onset seizures, myoclonic seizures, and primary generalized tonic-clonic seizures—with no approved indication for any psychiatric condition. 1

Significant Risk of Worsening Mood Symptoms

• The FDA label explicitly warns that levetiracetam causes behavioral abnormalities including depression, anxiety, hostility, and emotional lability. 1
• In pediatric patients, 37.6% experienced behavioral symptoms (agitation, depression, hostility, nervousness) compared to 18.6% on placebo, with 3.0% discontinuing due to psychiatric adverse events. 1
• In adults with myoclonic seizures, non-psychotic mood disorders (depression, depressed mood, mood swings) occurred in 6.7% on levetiracetam versus 3.3% on placebo. 1
• Depression was reported as an adverse event across multiple seizure types, with one case report documenting psychotic-like behavior with auditory hallucinations and suicidal thoughts requiring discontinuation. 1

Limited and Low-Quality Evidence for Mood Stabilization

• Only case reports and small open-label pilot studies suggest potential mood-stabilizing effects—no placebo-controlled trials exist. 4
• One case report described successful use after multiple treatment failures, but this represents the lowest level of evidence and cannot guide clinical practice. 5
• A systematic review concluded that levetiracetam presents an "intermediate risk" for depression (approximately 4% prevalence), higher than established mood stabilizers like lamotrigine (<1%). 6

What Should Be Used Instead

For Major Depressive Disorder

• Select second-generation antidepressants (SSRIs or SNRIs) based on adverse effect profiles, cost, and patient preferences. 2
• SSRIs are recommended as first-line treatment for mood disorders by the UK National Institute for Health and Care Excellence. 2
• Assess response within 6-8 weeks and modify treatment if inadequate response occurs. 2

For Bipolar Disorder

• Lithium, valproate, or atypical antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) are first-line for acute mania/mixed episodes. 3
• Lithium shows superior evidence for long-term maintenance therapy and reduces suicide attempts 8.6-fold. 3
• For bipolar depression, use olanzapine-fluoxetine combination or a mood stabilizer with careful addition of an antidepressant—never antidepressant monotherapy. 3

Critical Clinical Pitfalls to Avoid

Using Levetiracetam Off-Label for Mood Disorders

• The one case report of levetiracetam overdose in a patient using it for bipolar disorder resulted in respiratory depression requiring intubation, highlighting both the lack of established dosing for psychiatric conditions and serious safety concerns. 7
• Levetiracetam can cause acute aggression and severe behavioral abnormalities, particularly with dose increases, which resolved only after dose reduction or discontinuation. 8

Ignoring Evidence-Based Alternatives

• Established mood stabilizers (lithium, valproate, lamotrigine) have decades of evidence, FDA approval for psychiatric indications, and clear therapeutic monitoring protocols. 3
• Second-generation antidepressants have demonstrated equivalent efficacy for depression with well-characterized adverse effect profiles. 2

Inadequate Monitoring If Levetiracetam Is Already Prescribed

• If a patient is already taking levetiracetam for seizures and develops mood symptoms, recognize that the medication itself may be contributing to psychiatric deterioration. 1, 6
• Monitor closely for behavioral changes, depression, anxiety, and suicidal ideation, particularly within the first 4 weeks of initiation or dose changes. 1
• Consider switching to an antiepileptic with mood-stabilizing properties (valproate, lamotrigine, carbamazepine) if seizure control allows. 3, 6