Evaluation of major adverse events of clozapine based on accordance to an international titration guideline

Abstract

Introduction: Clozapine is the only antipsychotic approved for treatment-resistant schizophrenia, but without appropriate monitoring, it can be associated with potentially fatal outcomes. An International Adult Clozapine Titration Guideline categorizes patients into normal or slow metabolizers. Categorization provides clozapine titration schedules and recommends regular c-reactive protein (CRP) and clozapine concentration monitoring to reduce the risk of adverse drug reactions (ADRs). The impact of the guideline on clozapine ADRs has not been evaluated.

Methods: A retrospective chart review assessed clozapine titrations, laboratory monitoring, ADRs, and discontinuations for clozapine-naive adult inpatients at a single center from January 1, 2013, to June 1, 2022. Each patient's cumulative weekly clozapine dosage was compared with their guideline recommended dosage to create a percent accordance. Linear logistic regression evaluated the relationship between titration speed and the presence of an ADR, while descriptive statistics analyzed laboratory monitoring.

Results: Forty-three patients were included, with the majority being White males with schizophrenia. An inverse relationship existed between the last inpatient week clozapine dose percent accordance and the probability of an ADR. Nonobese patients were less likely than obese patients to experience an ADR (odds ratio = 0.17; 95% CI, 0.03-0.99). CRP and clozapine concentration monitoring was suboptimal.

Discussion: Based on our small retrospective review of primarily White males, more aggressive clozapine titrations did not increase ADRs. Future studies with more diverse samples are needed and should focus on specific ADRs, which may have increased occurrence with rapid titrations. Obese patients were at higher risk of ADRs, correlating with the guideline-recommended slower titrations for these patients.

Keywords: antipsychotic agents; clozapine; dose-response relationship; drug; drug-related side effects and adverse reactions; inflammation; schizophrenia spectrum and other psychotic disorders.

FIGURE 1

Probability of adverse drug reactions (ADRs) based on last week International Clozapine Titration Guideline (ICTG) percent dose accordance, cumulative ICTG percent dose accordance, and obesity status. Four binary logistic regression models evaluated the probability of ADR for obese and nonobese patients. Last week ICTG percent dose accordance was taken from the clozapine exposure for the last week inpatient, while cumulative ICTG percent dose accordance encompassed total clozapine exposure through the last inpatient week

FIGURE 2

Last week International Clozapine Titration Guideline (ICTG) percent dose accordance and cumulative ICTG percent dose accordance percentage by obesity status; age at administration by adverse drug reaction (ADR) status. (A) Last week percent accordance was taken from the clozapine exposure for the last week inpatient. On average, obese patients did have a higher last week percent accordance. One mild outlier existed, within median ± 1.5 × (Q3-Q1), in the non-ADR group. (B) Cumulative ICTG percent dose accordance encompassed total clozapine exposure through the last inpatient week. On average, obese patients did have higher cumulative ICTG percent dose accordance. One mild outlier existed, within median ± 1.5 × (Q3-Q1), in the non-ADR group. (C) Age in years at the time of admission was compared with ADR occurrence (yes or no). The patients in the ADR group were slightly older; the, average age in ADR group was 41.7 versus 38.9 years in the non-ADR group