Behavioral Side Effects of Depakote (Valproate) in Children with Epilepsy
While valproate is generally well-tolerated behaviorally in children with epilepsy, the most commonly reported behavioral side effects include minor transient behavioral difficulties, emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration, though these effects are typically less severe than those seen with phenobarbital. 1
Primary Behavioral and Psychiatric Effects
The FDA drug label for valproate identifies the following behavioral and psychiatric adverse events in pediatric epilepsy patients 1:
- Emotional upset and depression - reported as adverse events in clinical use
- Psychosis, aggression, hyperactivity, and hostility - documented in post-marketing surveillance
- Behavioral deterioration - can occur during treatment
- Confusion and personality disorder - reported in 1-5% of patients in controlled trials
Evidence from Controlled Trials
In randomized controlled trials of children with newly diagnosed epilepsy, those treated with valproate experienced only minor behavioral difficulties after one month of treatment, and importantly, these did not persist at six months. 2 This contrasts favorably with other antiepileptic drugs, particularly phenobarbital, which causes behavioral disturbances severe enough to necessitate discontinuation in 20-40% of pediatric patients. 3
Central Nervous System Effects
Beyond behavioral changes, valproate can cause CNS effects that may impact behavior indirectly 1:
- Sedation - occurs most commonly when combined with other antiepileptic drugs, and usually improves with dose reduction of concomitant medications
- Tremor - dose-related effect occurring in 25-57% of patients in controlled trials
- Somnolence - reported in 27-30% of patients
- Confusion and dizziness - less common but documented
Positive Behavioral Effects
Notably, some patients actually report behavioral improvements on valproate, including increased alertness, improvement of mood, and improved performance at school. 4 This suggests valproate may have mood-stabilizing properties that can be beneficial in some children with epilepsy.
Comparative Behavioral Profile
When compared to other antiepileptic drugs in pediatric populations 5:
- Valproate has a more favorable behavioral profile than phenobarbital, which should be avoided as initial monotherapy in children whenever possible due to overwhelming evidence of behavioral adverse effects
- Behavioral sequelae with valproate are minimal compared to other traditional antiepileptic drugs 6
- Minor behavioral difficulties that do occur are typically transient and resolve within the first few months of treatment 2
Clinical Monitoring Considerations
The American Academy of Child and Adolescent Psychiatry recommends baseline and periodic clinical assessment every 3-6 months for patients on valproate, which should include evaluation for behavioral changes. 7 Parents and caregivers should be educated about potential behavioral side effects at treatment initiation, though they should be reassured that serious behavioral problems are uncommon and often transient.
Important Caveats
- Rare cases of encephalopathy with confusion have occurred, particularly in patients with underlying urea cycle disorders, and can present with behavioral changes 1
- Maternal anxiety and depression are common in families of children with newly diagnosed epilepsy, which may be misattributed to medication effects 2
- Behavioral problems are common in children with epilepsy independent of medication, making it challenging to distinguish drug-related effects from disease-related issues 5