Clozapine Metabolism is Associated With Absolute Neutrophil Count in Individuals With Treatment-Resistant Schizophrenia

Abstract

Up to one-third of those with schizophrenia fail to respond to standard antipsychotics and are considered to have treatment-resistant schizophrenia, a condition for which clozapine is the only evidence-based medication. While up to 60% of treated individuals obtain therapeutic benefits from clozapine, it is currently underprescribed worldwide, partly because of concerns related to its broad adverse effect profile. In particular, the potential effects of clozapine on the immune system have gained relevance after a recent study showed that drug plasma concentrations were inversely correlated with neutrophil counts in individuals routinely undergoing treatment. Seeking to investigate this relationship in more detail, we extracted metabolic, immune, and genetic data from a UK cohort of long-term clozapine users linked to a clozapine monitoring service, CLOZUK2 (N = 208). Whilst a correlation analysis was compatible with the original results, a multiple linear regression accounting for dose and other confounding factors additionally allowed us to estimate the decrease in absolute neutrophil counts to approximately 141 cells/mm3 for every 0.1 mg/L increase in clozapine concentration. However, this association was attenuated after controlling for the metabolic ratio between clozapine and its main metabolite, norclozapine, which was itself negatively associated with neutrophil concentrations. Further analyses revealed that these relationships are likely moderated by genetic factors, as three pharmacogenomic SNPs previously associated to norclozapine plasma concentrations and the metabolic ratio (rs61750900, rs2011425 and rs1126545) were shown to be independently associated with a variation in neutrophil counts of about 400 cells/mm3 per effect allele. Such results are compatible with an effect of norclozapine, but not necessarily clozapine, on immune cell counts, and highlight the need for further investigations into the potential role of genetic determinants of clozapine pharmacokinetics in the occurrence of adverse effects during treatment.

Clozapine and COVID‐19 Vaccination: Effects on blood levels and leukocytes. An observational cohort study

“…Considering the negative association of clozapine/norclozapine ratio with neutrophil concentrations, observed decline of granulocytes may also be due to alterations in metabolization of clozapine. 16 Unfortunately, norclozapine levels were not analysed in measurements conducted by HPLC. Therefore, we were not able to correct for changes in clozapine/norclozapine ratio.…”

“…In order to avoid extra strain on patients and patient laboratory service centres, no baseline measurements of clozapine blood level, WBC and differential were taken on the day of administration of both COVID‐19 vaccinations. Considering the negative association of clozapine/norclozapine ratio with neutrophil concentrations, observed decline of granulocytes may also be due to alterations in metabolization of clozapine 16 . Unfortunately, norclozapine levels were not analysed in measurements conducted by HPLC.…”

“…Moreover, clozapine may be associated with secondary antibody deficiency (SAD), explaining the more frequent complications of a SARS‐CoV‐2 infection with pneumonia 15 . Increased clozapine blood levels (with a high metabolic ratio of clozapine/norclozapine) are associated with decreased neutrophils in long‐term recipients of clozapine with refractory schizophrenia 16 . Both genetic factors (with increased neutropenia in patients with schizophrenia of African ethnicity) and combination therapy with fluvoxamine, reducing the formation of norclozapine by CYP1A2 inhibition, are associated with high clozapine to norclozapine ratios 17 …”

Effect of Valproic Acid on the Metabolic Spectrum of Clozapine in Patients With Schizophrenia

“…[25][26][27][28] Interestingly, pharmacokinetic alterations of CLZ have been linked to absolute neutrophil count levels. [29][30][31] Furthermore, N-DMC has been suggested to have beneficial effect on cognitive impairments of schizophrenia because of N-DMC's exert effects of several receptors, for example, the muscarinic receptors, where it acts as a partial agonist. 32 As N-DMC may have procognitive and progranulocytotic properties, a VPA-mediated reduction in N-DMC may theoretically increase the risk of cognitive failure and neutropenia among CLZ-treated patients.…”

Pharmacokinetics and pharmacogenomics of clozapine in an ancestrally diverse sample: A longitudinal analysis and GWAS using clinical monitoring data from the UK

“…Pharmacogenomic approaches are established experimental designs for discovering novel predictors of drug metabolism and treatment response, often highlighting specific genetic markers among well-known biological pathways and enzymatic mechanisms 13 . Recent genome-wide association studies (GWAS) have pointed towards a small number of variants that could explain between 1% and 10% of the variance in clozapine pharmacokinetics after accounting for non-genetic factors 14,15 , and these may also have downstream relevance for ADRs 16 . Unfortunately, these studies have only been carried out in individuals of European ancestry, a clear limitation given the known diversity of drug-metabolising enzyme alleles worldwide, and the potential lack of transferability of genomic predictors across populations 13 .…”