Clozapine-Associated Generalized Seizure at Therapeutic Dose Without Prior Epilepsy: A Case Report

Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia but is associated with a dose-dependent reduction in seizure threshold. While seizures are typically linked to high doses or rapid titration, events at therapeutic doses remain clinically significant and poorly characterized, particularly in resource-limited settings.

We report a 35-year-old Ethiopian man with treatment-resistant schizophrenia stabilized on clozapine 300 mg/day for 8 months who presented with a first generalized tonic-clonic seizure. There was no prior seizure history. Laboratory evaluation and neuroimaging were unremarkable. Electroencephalography (EEG) demonstrated generalized spike-wave discharges with photoparoxysmal response, suggesting underlying epileptiform susceptibility. Clozapine serum levels were unavailable. After exclusion of alternative causes, the event was considered likely clozapine-associated. Clozapine dose was reduced to 200 mg/day and sodium valproate initiated. The patient remained seizure-free at 6-month follow-up with preserved psychiatric stability.

Clozapine may precipitate seizures at therapeutic doses in patients with latent epileptiform susceptibility. When therapeutic drug monitoring is unavailable, careful clinical assessment, EEG evaluation, and exclusion of alternative causes are essential. Dose reduction with anticonvulsant therapy may permit safe continuation of clozapine.