Title: Using Genetics to Personalise Antipsychotic Treatment
Funder: Department of Health and Social Care

Abstract: USING GENETICS TO PERSONALISE ANTIPSYCHOTIC TREATMENT More than 20 different antipsychotic medications are available in the UK. Drug choice and dose adjustments are empirical and it is common for patients to need several medication changes. However, there is compelling evidence that genetic factors influence response and adverse drug reactions [1]. For about 200 medications, including several antidepressants and a few antipsychotics, there are clinical guidelines and Food and Drug Administration (FDA) or European Medicines Agency (EMA) labels recommending dose adjustments based on genetic profile [2-8]. However, in NHS mental health practice we do not use pharmacogenetics testing yet, due to insufficient evidence of its clinical benefits and cost-effectiveness [9, 10]. AIMS To investigate if pharmacogenetics-guided antipsychotic treatment improves clinical outcomes. Does pharmacogenetics help to reduce adverse drug reactions? Is the pharmacogenetics intervention cost-effective compared to treatment as usual? Investigate the acceptability of pharmacogenetics amongst patients and clinicians. CLINICAL EVALUATION Participants: We will recruit 400 adult patients with psychosis of any sex and ethnicity who currently take antipsychotic medication. Intervention: We will genotype participants at the clinically accredited Health Services Laboratories. We will also use the UK Biobank Axiom Array in collaboration with the NIHR UCL Bio-Resource. We will provide the participants clinicians with the pharmacogenetics test results to help them adjust the dose of antipsychotic or consider an alternative medication based on the patient s individual genetic and clinical profile. Variants in CYP2D6, CYP2C19, CYP3A4, CYP1A2 and CYP3A5 genes have sufficient evidence/guidelines/drug labels to be clinically actionable or worth investigating [1]. We will invite all participants to consent to their data being included in the Clinical Record Interactive Search (CRIS) system at University College London and King s College London, already holding anonymised electronic mental health records for 530,000 patients [11]. Comparator - We will compare two groups of Clinical Record Interactive System (CRIS) participants: 400 patients receiving the pharmacogenetics-guided antipsychotic treatment (intervention). 1,600 patients taking antipsychotic treatment as usual. Participants in the intervention and treatment as usual arms will be group-matched by medication, age, sex, ethnicity and duration of illness. Follow up period: 12 to 24 months. Primary outcome: Number of days receiving acute care. Secondary outcomes: Body Mass Index (BMI), weight, HbA1c, lipid profile, prolactin, QT interval, QRISK [12]. Plasma levels of antipsychotic medication. Symptom burden. STATISTICS We will use linear mixed models to compare the two treatment groups on the outcomes (clinical outcomes, adverse drug reactions and healthcare resource use). We will adjust all models by age, duration of illness, sex and ancestry. HEALTH ECONOMICS From project data and literature, we will run a within trial cost-effectiveness analysis and a modelled evaluation of the long-term impact of the intervention on care for people with psychosis. ACCEPTABILITY We will investigate patients and professionals experience of the intervention using qualitative methods. NHS ADOPTION &ndash; PATIENT BENEFIT The Genomics England Pharmacogenetics Working Group is developing a new pharmacogenetics service for the NHS. The study we propose will provide evidence for the inclusion of mental health drugs in this service.

Lay abstract: USING GENETICS TO PERSONALISE ANTIPSYCHOTIC TREATMENT BACKGROUND Over 20 different antipsychotic drugs are available in the UK, all of them effective. Antipsychotics however, can cause undesirable side effects such as sleepiness, shaking, sexual dysfunction, weight gain, high cholesterol and diabetes. Our genes influence how we respond to medications and our chances of developing side effects. In particular, a group of genes known as CYP influence the speed at which the liver breaks down and eliminates some antipsychotic drugs. We want to use CYP gene tests to identify the more drug-sensitive patients, who would need lower doses of certain antipsychotics or people who may benefit from an alternative antipsychotic. CYP gene tests are available, but not used in mental health services yet. AIMS Evaluate if CYP gene testing can improve patient recovery Can CYP testing reduce side effects? Can testing save costs for the NHS? Is CYP testing acceptable to patients and clinicians? STUDY DESIGN We will recruit 400 adults with psychosis of any sex and ethnicity. We will test their CYP gene profile in a clinical lab and send the results to the doctor prescribing their antipsychotic. We will invite participants to join the Clinical Record Interactive Search (CRIS) system, which holds anonymised health records for 530,000 people treated at two NHS Foundation Trusts: Camden & Islington and South London & Maudsley. We will compare two groups of Clinical Record Interactive Search (CRIS) participants: 400 people taking antipsychotic treatment guided by their genetic profile (intervention). 1,600 people taking antipsychotic treatment as usual. All patients and their clinicians will be able to use any antipsychotic drug without restrictions. However, only the participants in the intervention group and their doctors will know their genetic profile in order to inform medication and dose choices. We will measure side effects (weight, cholesterol, glucose) and use of healthcare resources after 12 to 24 months. We will investigate if CYP gene testing is beneficial and/or cost saving. We will interview patients and clinicians to seek their opinion about using genetics to inform medication decisions. PATIENT & PUBLIC INVOLVEMENT The UCL Service User Research Forum (SURF) helped to design this study. The SURF co-applicant and collaborators will contribute throughout the study including recruitment, analysis and dissemination. Training opportunities and funding are available to SURF researchers. DISSEMINATION Through a study website, press releases, newsletters, scientific and newspaper articles, public talks, conference posters and presentations. We will develop a free online training module on pharmacogenetics for mental health clinicians. IMPLICATIONS This study will show whether genetic testing helps to improve patient outcomes, NHS services and patient satisfaction. This technology could bring major benefits to the health and wellbeing of people who take antipsychotics.

Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: MENTAL HEALTH