The research, published in PLOS Genetics, was led by University of Bristol researchers funded by the National Institute for Health and Care Research (NIHR) and the Medical Research Council (MRC). They looked at 80 reported side-effects of 6 commonly prescribed antipsychotic drugs.
The team used a new method they have developed. It combines publicly available data to uncover the mechanisms of the reported side effects, including:
- Drug binding affinity
- Genome Wide Association Studies (GWAS)
- Gene expression quantitative trait locus (QTL) data
They believe this approach could be applied to other drug types and could be a useful tool in the drug development pipeline.
Linking drug targets with genetic signals
Drugs work by targeting different receptors in human cells. These are known as drug targets. By linking the targets of the antipsychotic drugs with genetic signals, they identified the likely biological mechanisms behind 36 side-effects. Most side-effects were due to the drug interacting with unintended (or off-target) receptors.
Clozapine, a widely used antipsychotic, had the most extensive side-effects. They found that its known side-effects, like weight gain and reduced white blood cell counts, could be explained by its action on specific receptors.
Andrew Elmore, Senior Research Associate at the NIHR Bristol Biomedical Research Centre and lead author of the study, said:
“Our method helps to pinpoint which side-effects are likely caused by which drug actions. This offers insights that could improve drug safety and inform clinical decisions.
“This framework can also be applied to other medications and stages of drug development to better understand both intended and unintended effects.”
Improving drug discovery and clinical trials
The team believe their approach could be adopted into drug discovery pipelines, as a useful indicator of the potential side-effect profile of drugs in early development. Predicting which receptors cause which side-effects could help reduce side-effects by minimising binding to those receptors.
It could also help improve clinical trials by predicting side-effects at the study design stage. Side-effect profiling would inform what data should be collected during the trial.
It also has benefits for existing drugs. Understanding which receptor is causing a side-effect opens new drug repurposing possibilities.
Improving prescribing and patient care
It could also inform drug choice for patients and clinicians. Clinicians would have a clearer idea of both drug-specific side-effects, and of which alternatives may have the same side-effects. This could avoid switching patients that have suffered a particular side-effect to an alternative that likely has the same side-effect.
Paper
Genetic Inference of On-target and Off-target Side-effects of Antipsychotic Medications
Andrew Elmore, Aws Sadik, Lavinia Paternoster, Golam Khandaker, Tom Gaunt, Gibran Hemani
Published in PLOS Genetics