Pharmacokinetics and pharmacogenomics of clozapine in an ancestrally diverse sample: a longitudinal analysis and genome-wide association study using UK clinical monitoring data

Rare Variants in Pharmacogenes Influence Clozapine Metabolism in Individuals with Schizophrenia

“…Our primary analysis show that a greater burden of rare damaging variants in the PharmaADME core gene set, which contained 30 genes associated with general drug metabolism ( Table 1 ), was associated with significantly lower clozapine and norclozapine plasma concentrations ( Figure 1 ). Furthermore, the burden of rare variants in this set explains 0.40% of the variability of this phenotype ( Table 3 ), a similar figure to the 0.61% variance explained by a PRS generated from genome-wide significant loci in a recent clozapine metabolism GWAS 9 . In the CLOZUK2 sample, the effects of each rare damaging allele in this set were approximately equivalent to a 35 mg reduction in clozapine daily dose.…”

“…A related issue is that while the CLOZUK2 cohort is derived from the diverse current population of the UK, the majority of individuals for which both WES and clozapine levels monitoring data were available were of European ancestry. Given that individuals of other biogeographical ancestries are known to have different clozapine pharmacokinetic profiles 9 , our study cannot assess a potential rare variant contribution to those known ancestral differences, and its results might not be straightforwardly transferrable to non-European populations. We note, however, that consistency of variant effect sizes across populations is a reasonable assumption for pharmacogenes 52 and that the occurrence of deleterious variation in these gene sets is frequent (though individually rare) across continental ancestries 53 .…”

“…Drug pharmacokinetics can vary substantially between people, with both environmental and genetic factors partially explaining these differences. While 40% of the inter-individual variability in clozapine metabolism has been related to demographic, lifestyle and clinical predictors (sex, age, body weight and smoking) 8 , the few genetic studies performed to date have already found a small number of common genetic variants explaining up to an extra 3%-8% 9 . As the effects of these markers are additive to those of environmental predictors 10 , their discovery is a first step towards eventual pre-emptive pharmacogenomic (PGx) interventions to personalise and improve clozapine treatment protocols.…”

Precision medicine in cardiovascular therapeutics: Evaluating the role of pharmacogenetic analysis prior to drug treatment

“…A meta-analysis of 11 articles that included PRS for 30 traits found an association between PRS and response to antidepressant treatment in patients with unipolar MDD [61], and indeed, PRS scores have been widely used in the field of psychotic disorder treatment [62]. As an example, a PRS based on eight pharmacogenomic variants in five different genetic loci was recently shown to explain 7.3% of the variance in clozapine metabolic ratios in different ancestry groups [63]. PRSs have also been shown to be effective in categorizing patients as responders or non-responders to ezetimibe [64].…”

The emergence, implementation, and future growth of pharmacogenomics in psychiatry: a narrative review

“…According to a recent systematic review, 59% (30/51) of all studies using polygenic scores in PGx have been conducted within the area of mental and behavioral diseases (Johnson et al, 2022). Some of the most notable of these studies have applied this approach to antidepressant (Li, Tian, Hinds, & Team, 2020; Pain et al, 2022), clozapine (Okhuijsen-Pfeifer et al, 2022; Pardiñas et al, 2023), and lithium (Amare et al, 2023) response but results are mixed and the variance explained by polygenic scores have been modest (e.g. <10%).…”