Clozapine-associated neutropenia among patients with treatment-resistant schizophrenia in Saudi Arabia: a retrospective cohort study

Clozapine (CLZ) is an essential antipsychotic medication for treating resistant schizophrenia; however, it carries serious side effects, including severe neutropenia and agranulocytosis. As a result, frequent laboratory monitoring is necessary both before starting CLZ and during therapy. This study aims to evaluate the incidence and factors associated with neutropenia and agranulocytosis and its associated laboratory monitoring cost in the Saudi population with treatment-resistant schizophrenia (TRS). A retrospective cohort study included Saudi adult patients with TRS who began CLZ treatment in the outpatient setting at Eradah Complex and Mental Health Hospital (ECMHH) from January 2005 to August 2023. The primary outcome was to evaluate the incidence of neutropenia and agranulocytosis, while assessing factors associated with neutropenia and the cost of regular laboratory monitoring as secondary outcomes. All patients were followed for a minimum of one year after starting clozapine treatment. Descriptive, inferential, and logistic regression analysis were utilized as appropriate. During the study period, 482 patients were screened, and 188 of them met the eligibility criteria for inclusion. The incidence of neutropenia within one year of initiating CLZ was found to be 14.4%, affecting 27 patients. Among these, 10.6% (20 patients) experienced mild neutropenia, while 3.7% (7 patients) had moderate neutropenia. No cases of severe neutropenia or agranulocytosis were observed. In the final multivariable model, a high baseline ANC was associated with lower odds of neutropenia within one year of clozapine initiation (adjusted odds ratio [aOR] 0.14; 95% CI: 0.06–0.32). Concomitant amitriptyline use was also associated with higher odds of neutropenia (aOR 7.37; 95% CI: 1.54–35.29). Male gender trended toward lower odds of neutropenia (aOR 0.33; 95% CI: 0.11–1.04), while a higher initial clozapine dose trended toward higher odds (aOR 1.01; 95% CI: 0.99–1.02); however, neither association reached statistical significance. Moreover, the median number of visits for laboratory monitoring was 16 (interquartile range [IQR]: 11–25), with a median monitoring cost of 3,200 SAR (IQR: 2,200-5000 SAR). Within the first year of CLZ initiation, neither severe neutropenia nor agranulocytosis was detected in our population. However, there were additional costs associated with the need for frequent monitoring. Low baseline ANC and concomitant amitriptyline use were associated with higher odds of neutropenia. Because these exploratory findings cannot establish causality, larger cohort studies and clinical trials are required to confirm the results. Not applicable.