The Effect of Levetiracetam and Valproic Acid Treatment on Anger and Attention Deficit Hyperactivity Disorder Clinical Features in Children and Adolescents with Epilepsy: A Prospective Study

Antiseizure medications (ASMs) can potentially trigger psychobehavioral adverse events associated with the onset or exacerbation of psychiatric symptoms such as irritability, aggression, and hyperactivity. The objective of this study was to evaluate the effects of levetiracetam and valproic acid on changes in clinical features of anger, attention deficit hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD). The purpose was to furnish guidance on rational drug selection in children and adolescents with epilepsy to minimize psychiatric comorbidity in the treatment of epilepsy.

This was a prospective, observational, cohort study involving treatment-naïve children aged 7–18 years with newly diagnosed generalized or focal epilepsy who were prescribed levetiracetam or valproic acid as monotherapy for a 6-month period and regularly followed up. Psychiatric assessment was conducted at the time of the new epilepsy diagnosis and at the six-month follow-up. These assessments were performed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children Current and Lifetime Version (DSM-5), a structured psychiatric interview, as well as the State-Trait Anger Expression Style Inventory and Turgay DSM-IV Based Disruptive Behaviour Disorders Screening and Rating Scale. Anger subscores, ADHD symptoms, change in diagnosis, focal and generalized epilepsy groups, continuous seizures and seizure-free periods before and 6 months after treatment with valproic acid and levetiracetam were compared.

A total of 50 children, 25 in the valproic acid group and 25 in the levetiracetam group, with a mean age of 11.92 ± 3.08 years, were included in the study. There was a statistically significant increase in the ADHD subscale score post-treatment among patients receiving levetiracetam (p = 0.045) and valproic acid (p = 0.034) compared with pre-treatment. The change in both anger-in and anger-out expression scores with treatment was significantly higher in patients receiving levetiracetam (p = 0.035) compared with those receiving valproic acid (p = 0.026). Statistically, there was a significant difference in the diagnostic criteria of the levetiracetam group pre- and post-treatment (p = 0.026). The proportion of patients in whom the diagnostic criteria for ADHD+ODD were fulfilled increased from 16% before treatment to 48% after treatment, a statistically significant increase (p = 0.026).

This study found an increase in internalized anger features and ADHD symptom severity in children with epilepsy treated with valproic acid and levetiracetam. In those prescribed levetiracetam, there was a statistically significant rise in the proportion meeting the diagnostic criteria for ADHD + ODD. Our research is one of the first to prospectively examine the psychiatric assessment of children diagnosed with epilepsy. The remarkable results demonstrate changes in psychiatric diagnoses associated with the treatment of levetiracetam and valproic acid. Furthermore, a considerable rise in ADHD symptoms was observed in those treated with valproic acid.