Siobhan Lock was a recipient of Mental Health Research UK’s John Grace QC PhD Scholarship in 2022. She started at Cardiff University just last September and she writes here about her enthusiasm for her project and why it is important.
Have you ever wondered why some people respond to medication differently than others? Why do some improve, and others develop side effects? Understanding how genetic differences between people might affect these responses is something that really interests me. Part of my PhD project will involve looking at how genetic variation affects drug response and side effects in people with schizophrenia.
Schizophrenia is important to study because it is a complex health problem that can be very distressing to live with. Symptoms of schizophrenia can vary but often include psychotic experiences of hallucinations (seeing or hearing things that others do not experience) and delusions (false, often bizarre beliefs), but also reduced motivation, movement problems, or cognitive impairment. Schizophrenia is often treated with antipsychotic medication. There is variation in response to these medications, so what works for one person is not necessarily helpful for another. In some cases, people may not respond at all to standard antipsychotic medications, and when this occurs, a person is said to have treatment-resistant schizophrenia. This is a pretty big problem and one that I’m hoping to investigate over the next few years.
Clozapine is the only antipsychotic drug which is proven to help improve symptoms in people with treatment-resistant schizophrenia (Tiihonen et al. 2017). However, clozapine can also have serious side effects. Notably, causing a reduction in the number of neutrophils - a type of white blood cell important to immune response. When searching for genetic variants associated with neutropenia in individuals of African genetic ancestries, what researchers found was a strong genetic link to a variant called the Duffy-Null (Legge & Pardiñas et al. 2019).
The Duffy-Null genotype was already associated with low neutrophil counts. But what’s interesting is that it is benign. So, these low neutrophil levels are totally normal for individuals with this genotype (Atallah-Yunes et al. 2019). This was important because it meant that many individuals with schizophrenia were being removed from clozapine medication for having a ‘side-effect’, which was in fact their normal blood levels due to this genetic variant. Knowing this is really important because it could help to make blood monitoring guidance more inclusive of people with lower baseline neutrophil counts and therefore help to widen access to one of the most effective antipsychotic medications currently available. All in all, this sort of research has the potential to be really useful for people with schizophrenia. In the case of the Duffy-Null genotype, we can use this knowledge to help guide clinical decision-making around an individual’s clozapine use.
But there’s more still that we can do! For example, if we know that there are genetic markers that make someone less likely to be responsive to a certain medication, we can adapt their treatment options accordingly. Equally, if we know from genetic predictors that someone is more likely to experience unpleasant side effects from certain antipsychotics, we can offer them alternatives. People may feel less like medication is a long experimentation of different drugs and doses, which could in turn improve patient recovery and their trust in mental health services. The ultimate goal of this would be for people with schizophrenia to be offered an antipsychotic that has the best chance of working well for them on their first presentation for help.
It is incredibly exciting to see the almost endless applications of such research into the genetic underpinnings of diverse disorders, such as looking towards developing specialised treatments that can help benefit people and communities. I am very happy to be working with a group that has such a great deal of experience and knowledge; it’s always great to get the chance to learn from some of the top researchers in the field. Further down the line, I hope that this will equip me with the knowledge and abilities to contribute in some tiny way to our understanding of the genetics of schizophrenia.
Atallah-Yunes, S.A., Ready, A. and Newburger, P.E. 2019. Benign ethnic neutropenia. Blood Reviews 37, p. 100586. doi: 10.1016/j.blre.2019.06.003.
Legge, S.E. and Pardiñas A.F. et al. 2019. A genome-wide association study in individuals of African ancestry reveals the importance of the Duffy-null genotype in the assessment of clozapine-related neutropenia. Molecular Psychiatry 24(3), pp. 328–337. doi: 10.1038/s41380-018-0335-7.
Tiihonen, J. et al. 2017. Real-World Effectiveness of Antipsychotic Treatments in a Nationwide Cohort of 29 823 Patients With Schizophrenia. JAMA Psychiatry 74(7), pp. 686–693. doi: 10.1001/jamapsychiatry.2017.1322.