Background
Clozapine is the only approved medication for treatment-resistant schizophrenia (TRS). While it is highly effective, not all patients respond the same way and some experience severe side effects. One key factor influencing clozapine’s effects is how the body metabolises the drug, but there is limited knowledge about the genetic factors involved.
This study aimed to explore whether rare genetic variations in genes related to clozapine metabolism affect drug levels in the blood. Researchers analysed whole-exome sequencing data from 2,062 patients with schizophrenia taking clozapine in the UK, using 6,585 pharmacokinetic tests (which measure how drugs are processed in the body).
Results
The study found that rare genetic variants in drug metabolism-related genes were linked to lower clozapine levels in the blood. The effect of a single damaging genetic variant was estimated to be similar to reducing a patient’s daily clozapine dose by 35 mg.
One of the strongest genetic links was found in CYP1A2, a gene that produces an enzyme responsible for breaking down clozapine into its metabolite, norclozapine. Variants in this gene had the most significant impact on clozapine metabolism.
Conclusions
These findings suggest that rare genetic differences can significantly affect how clozapine is processed in the body, influencing both treatment effectiveness and side effects. Current efforts to personalise clozapine treatment using pharmacogenomics (the study of how genes affect drug response) could benefit from including these rare genetic variants, expanding beyond the commonly studied pharmacogenetic markers. This research brings us closer to tailoring clozapine treatment to individual patients based on their unique genetic makeup.
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