A systematic review of clozapine‐associated inflammation and related monitoring

Abstract

Clozapine is an effective antipsychotic medication used for treatment‐resistant schizophrenia. However, it is underutilized due to rigorous hematologic monitoring requirements and many adverse drug reactions. Publications have highlighted the occurrence of inflammatory reactions, some life‐threatening, particularly during the early stages of clozapine treatment. Although guidelines have suggested monitoring for inflammatory processes during clozapine initiation, screening in clinical practice is not universal. This systematic review aimed to investigate the relationship between clozapine and inflammation and assess the importance of monitoring for inflammatory reactions. A comprehensive literature search yielded 6,915 unique publication records after removal of duplicates. After a rigorous screening process, 75 publications were included in the review, which focused on three main aspects: i) the impact of clozapine on inflammatory markers, ii) monitoring cardiac and other organ function during clozapine‐associated inflammatory processes, and iii) monitoring non‐specific signs and symptoms of inflammation. Elevated levels of C‐reactive protein (CRP) and several proinflammatory cytokines have been observed in association with clozapine treatment. However, the practicality of measuring specific markers in clinical practice remains uncertain. Current evidence supports monitoring CRP levels during the first 4 to 8 weeks of treatment, especially to facilitate myocarditis screening. Further research is needed to establish clinically‐relevant CRP thresholds for intervention. The implementation of monitoring protocols during the early phase of clozapine treatment may mitigate adverse reactions and allow for continued use of clozapine. Future studies should also explore the association between clozapine‐associated inflammation and pneumonia, as well as investigate the impact of inflammation on clozapine metabolism to predict the need for dose adjustment. These endeavors may facilitate the development and implementation of evidence‐based guidelines for the monitoring of clozapine‐associated inflammation.

Impact of patient-specific factors on clozapine metabolism in individuals with treatment-resistant schizophrenia or schizoaffective disorder

“…Initiation of clozapine treatment is associated with inflammation, including but not limited to myocarditis, which requires close monitoring. CRP measures have been recommended at baseline prior to initiation of clozapine and weekly throughout the initial few weeks following drug commencement ( Leung et al, 2023 ). Notably, compared to the general population, a diagnosis of schizophrenia and common comorbidities like metabolic syndrome are linked to greater levels of pro- and anti-inflammatory cytokines in the bloodstream as well as persistently elevated CRP ( Goldsmith et al, 2016 ; Ridker et al, 2003 ).…”

Patterns of C-reactive protein trends during clozapine titration and the onset of clozapine-induced inflammation: a case series of weekly and daily C-reactive protein monitoring

“…However, no clear criteria exist for clinicians to determine when to cease increasing the clozapine dosage to avoid clozapine-induced inflammation ( 15 ). Furthermore, the extent to which weekly CRP monitoring can be used to detect elevated CRP levels before the onset of clozapine-induced inflammation remains unclear.…”

“…Daily CRP measurements were taken at approximately 10 am using a Yumizen M100 Banalyst (measurable range 0.1-20 mg/dL; Kyoto, Japan) via finger capillary blood sampling. Previous studies have not provided clear parameters for the threshold of elevated CRP that poses a risk for the development of clozapine-induced inflammation (15). However, previous studies have indicated that the average CRP level is approximately 0.5 mg/dL in patients using clozapine (16)(17)(18)(19).…”