De Novo Seizures, Obsessive Compulsive Symptoms and Neutropenias in Patients on Clozapine: A Retrospective Cohort Study

Abstract

Background: Clozapine has well-documented inter-ethnic variations in pharmacokinetics. There is a paucity of data about clozapine use and associated adverse events such as seizures, obsessive compulsive symptoms, neutropenia, and agranulocytosis, from India. Methods: This retrospective cohort study followed up 228 patients initiated on clozapine in a tertiary care referral center in India for an average of 10 years. We calculated incidence rates of new-onset seizures, new-onset obsessive compulsive symptoms, agranulocytosis, and neutropenia. We collected data on doses of clozapine used and serum assays and calculated concentration-to-dose (C/D) ratios. We also collected relevant clinical details about clozapine-induced seizures. Results: In the sample, 16.8% had new-onset seizures, 12.3% had new-onset OC symptoms, 2.7% had neutropenia, and 0.9% had agranulocytosis. The mean C/D ratio was 2.09 (SD = 1.8). Almost half (46.3%) of available serum assays were in the supra-therapeutic range. Seizures were associated with a higher clozapine dose at one year (OR = 1.003; 95%CI = 1.000–1.006; P value = 0.045) and the presence of positive psychotic symptoms at one year (OR = 4.214; 95%CI = 1.894–9.373; P < 0.001). Conclusion: Compared to existing literature, Indians have a higher rate of clozapine- related seizures and need lower doses to reach therapeutic serum levels.

Reflections on the Lack of Consideration of Ethnic Ancestry to Stratify Clozapine Dosing

“…29 The clinical relevance of overdosing patients of Asian ancestry by using doses recommended for patients of European ancestry is finally reaching the literature. Recently in India, Chichra et al 126 completed a retrospective review of a cohort of 288 patients initiated on clozapine of which 38 (17%) had newonset seizures during clozapine treatment. These patients had significantly higher mean clozapine doses at 1 year of followup (373±120 vs. 319±120 mg/day) and this remained significant after adjusting for age and sex.…”