Largest genomic study of it's kind identifies improvements in schizophrenia medication for those who are of Asian and African descent

A study led by researchers at Cardiff University provides new evidence suggesting how improvements could be made to the prescription of medications for those with schizophrenia who are of Asian and African descent.

A team of researchers at the Centre for Neuropsychiatric Genetics and Genomics at Cardiff University has investigated data from over 4,500 individuals taking the antipsychotic clozapine, in one of the largest genomic studies of its kind published to date. The study was supported by grants from the Medical Research Council (part of UK Research and Innovation), the European Commission and the Academy of Medical Sciences.

Clozapine is the only licensed medication for treating schizophrenia symptoms that do not respond to other therapies, a presentation known as treatment-resistant schizophrenia that affects up to 30% of those with this mental health condition.

As with most drugs used in psychiatry, finding the dose of clozapine that works best for a given person can take weeks or months of treatment. During this time, clozapine might not work as well as it could: doses that are too low often have little or no impact on the symptoms of schizophrenia, while doses that are too high might put a person at risk of adverse reactions.

It is not currently possible to predict how people will respond to clozapine, but one of the hopes of the field of personalised medicine is that genetic information might eventually help in doing so.

Following this idea, this study was designed to explore the role of genetic variation in clozapine metabolism, the set of biological processes involved in how the drug is processed by the human body.

The data behind it comes from Cardiff University’s CLOZUK project, a large dataset of clinical and genetic information from individuals who were prescribed clozapine across the UK. Due to the large amount of people involved in the study, one of the first analyses performed was to determine their genetic ancestry, a measure of similarity to people who live in different regions of the world.

About 15% of participants were genetically close to populations in Africa and Asia, totalling a greater number of non-European individuals than reported in clozapine genetic studies to date. This was considered an important step towards achieving a better representation of the diversity of clozapine users in scientific research.

Dr Djenifer Kappel, postdoctoral researcher and co-author of the study, added some context:

“95% of the samples used in all published medical genetic studies come from Western European individuals. Until very recently it was common to discard information from those of non-European backgrounds, making them extremely underrepresented.

"This was done over concerns that it could make results difficult to interpret. But such a practice was challenged, has changed, and the experimental and statistical methods we now use are finally able to embrace the diversity of humankind.”

Analysing over 16,000 blood monitoring records collected during clozapine treatment, the team found evidence that those of Asian descent metabolised clozapine differently to European individuals.

This finding mirrored reports by other international research teams and reinforced recent clinical recommendations aimed to improve clozapine prescriptions for Asian individuals.

Interestingly, people of sub-Saharan African genetic ancestry were also found to differ from Europeans in their clozapine metabolism, but this was a novel and unexpected discovery.

“Differences in clozapine metabolism have not been shown in African populations before. Not accounting for these differences in clinical settings might make people less likely to respond to clozapine, in turn making them more likely to abandon this treatment. This may partly explain why other studies have reported low utilisation of clozapine in those of African descent. However, as with every scientific finding reported for the first time, validation in an independent cohort is required," commented Milly Roberts, Bioinformatics MSc and co-author of the study.

Finally, the researchers looked for specific genetic variants with effects on clozapine metabolism.

Eight regions of the human genome were found harbouring these variants. Most of the genes pinpointed had some biochemical evidence of being involved in clozapine metabolism, although they had rarely appeared in the results of genetic research due to the limitations of previous investigations.

The study discussed how these findings could eventually become useful in the psychiatric clinic.

Dr Antonio Pardiñas elaborated on these findings.

"For this purpose, a small number of genes and variants seem to be worthy of consideration, and the ancestral background we all bear in our genome should not be disregarded either. But these insights cannot contribute to any change in clinical practices without going through the gold-standard testing of clinical trials.

"While those are designed, other open questions remain: What do these genetic variants mean for people who carry them and are eventually prescribed clozapine? Do they respond better to the drug or worse? Are they at risk of an adverse reaction or are they less likely to have one? We don’t have the data to answer these questions yet, but we’re working hard to generate it."

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