Seizure side effect of clozapine

Clozapine and Seizures (Plasma Levels & Dosing)

Based on conflicting evidence, clozapine-induced seizures are not solely based on total dose or serum concentration. The utility of clozapine serum concentration for the purpose of seizure prevention is debated within the literature, mainly because of the lack of a well-established concentration threshold. It would be a safe assumption that seizure is more likely at higher concentrations (i.e. > 1000 ng/mL or > 3057 nmol/L), but similar to total oral dose, seizures still occur at lower concentrations (i.e. < 300 ng/mL or < 900 nmol/L).

Caution and close monitoring should be used for patients with seizure history or predisposing factors. For patients on clozapine experiencing seizures, this is never grounds for discontinuation. Management should include lowering or dividing the clozapine dose, prescribing valproate or another anti-epileptic drug without effect on myelopoetic cells.

Rates of seizures by dosing groups during early clozapine studies

<300 mg/d

300-599 mg/d      

≥ 600 mg/d

1991 (N= 1481)




1994 (N= 5629)




1994 (N= 5629)*




* Excluding patients with prior seizure history



  • Devinsky, O., Honigfeld, G., & Patin, J. (1991). Clozapine-related seizures. Neurology, 41, 369-371.
  • Meyer, J.M. & Stahl, S.M. (2020). The clozapine handbook. Cambridge University Press.
  • Nielsen J, et al. (2013). Termination of clozapine treatment due to medical reasons: When is it warranted and how can it be avoided? Journal of Clinical Psychiatry, 74, 603-613.
  • Pacia, S.V., Devinsky, O. (1994). Clozapine-related seizures: Experience with 5,629 patients. Neurology, 44, 2247-2249.
  • Schoretsanitis, G., Kane, J.M., Ruan, C.-J., Spina, E., Hiemke, C. (2019). A comprehensive review of the clinical utility of  and a combined analysis of the clozapine/norclozapine ratio in therapeutic drug monitoring for adult patients. Expert Review of Clinical Pharmacology, 12(7), 603-621. doi: 10.1080/17512433.2019.1617695
  • Williams, A.M. & Park, S.H. (2015). Seizure associated with clozapine: incidence, etiology, and management. CNS Drugs, 29, 101-111.
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