Treatment resistance and drug side effects in schizophrenia

Schizophrenia is a mental health condition where people may see, hear or believe things that aren’t real. People living with schizophrenia usually require lifelong treatment. Unfortunately, not everyone diagnosed with the condition will respond to the treatment they are given. Treatment-resistant schizophrenia affects a significant proportion of patients and means they will continue experiencing symptoms despite being given medication.

Clozapine is used to treat treatment-resistant schizophrenia. It is usually given to people who haven’t responded to other treatments. However, it is not a first-line drug of choice because of the number of severe side effects patients frequently report developing after taking it.

We are interested in determining whether genetics has an impact on treatment resistance and drug side effects in schizophrenia. We are also interested in using genetic data to more deeply understand drug side effects, and possibly guide new drug discovery.

Project aims

During this project we:

• Identified genetic differences between patients diagnosed with schizophrenia and those who are resistant to treatment
• Explored whether these differences can be linked to certain outcomes such as the side effects patients may be likely to develop because of treatment

Our findings

We used a new method combining 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 had the most extensive side-effects. We found that its known side-effects, like weight gain and reduced white blood cell counts, could be explained by its action on specific receptors. 

What we hope to achieve

Overall, we hope that this project will help us:

• understand more about the genetic background of schizophrenia
• understand more about the effects of certain medications
• inform and shape the development of new drugs with fewer side effects

Improving drug discovery and clinical trials

This 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.