CRESTAR · Pharmacogenomic biomarkers as clinical decision making tools for clozapine treatment of schizophrenia

Treatment resistant schizophrenia (TRS) is the most disabling of all psychiatric illnesses, affecting about 1/3 of patients (~1 million Europeans), a considerable economic and social burden. First-line treatments include atypical (e.g. olanzapine) and typical (e.g. haloperidol) antipsychotics. The original atypical, clozapine, is a final option, and although it is the only antipsychotic shown to be effective in TRS, about half of TRS patients are also resistant to clozapine. CRESTAR is an SME-driven projected, focusing on the development of pharmacogenomic biomarkers for schizophrenia. It aims to develop tools to predict i) who will NOT respond to usual antipsychotics, indicating treatment with clozapine as early as possible, ii) the 1% of patients who will develop potentially fatal side effects, agranulocytosis, which is the main factor limiting clozapine use, and diabetic ketoacidosis, occurring in up to 2% of patients, and often fatal. We will also predict patients likely to be non-responders to all antipsychotics, i.e. extreme TRS, so that they can be stratified in clinical trials. CRESTAR will address these questions by examining genome-wide association data, genome sequence, epigenetic biomarkers and epidemiological data in European patient cohorts characterized for treatment response, and adverse drug reaction using data from clozapine therapeutic drug monitoring and linked National population medical and pharmacy databases, alongside existing European projects (e.g. PSYCNVs and EU-GEI) national initiatives (e.g. UK10K genome sequencing) to identify predictive factors. In parallel CRESTAR will perform health economic research on potential benefits, and ethics and patient-centered research with stakeholders. The outcome of CRESTAR will be a genomic test and associated clinical decision making tools, designed to improve pharmacological treatment of schizophrenia in both efficacy and safety, piloted with existing and new clinical trials such as OPTiMiSE.