Sergi Mas ^1* Laura Julià ¹ Manuel Jesus Cuesta ² Benedicto Crespo-Facorro ³ Javier Vazquez ⁴ Carlos Spuch ⁵ Ana González Pinto ⁶ Angela Ibañez ⁷ Judit Usall ⁸ CRISTINA ROMERO ⁹ Ana Catalan ¹⁰ Anna Mane Santacana ¹¹ Miquel Bernardo ¹²

• ¹ University of Barcelona, Barcelona, Spain
• ² Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Navarre, Spain
• ³ Virgen del Rocío University Hospital, Seville, Spain
• ⁴ Marqués de Valdecilla University Hospital, Santander, Cantabria, Spain
• ⁵ Instituto de Investigación Sanitaria Galicia Sur (IISGS), Vigo, Spain
• ⁶ Hospital Universitario Alava, Alava, Spain
• ⁷ Ramón y Cajal University Hospital, Madrid, Madrid, Spain
• ⁸ Sant Joan de Déu Research Institute (IRSJD), Esplugues de Llobregat, Spain
• ⁹ University of Cádiz, Cádiz, Spain
• ¹⁰ Basurto University Hospital, Osakidetza Basque Health Service, Bilbao, Basque Country, Spain
• ¹¹ Hospital del Mar Medical Research Institute (IMIM), Barcelona, Catalonia, Spain
• ¹² Hospital Clinic of Barcelona, Barcelona, Catalonia, Spain

The application of personalized medicine in patients with first-episode psychosis (FEP) requires tools for classifying patients according to their response to treatment, considering both treatment efficacy and toxicity. However, several limitations have hindered its translation into clinical practice. Here, we describe the rationale, aims and methodology of Applied Pharmacogenetics to Predict Response to Treatment of First Psychotic Episode (the FarmaPRED-PEP project), which aims to develop and validate predictive algorithms to classify FEP patients according to their response to antipsychotics, thereby allowing the most appropriate treatment strategy to be selected. These predictors will integrate, through machine learning techniques, pharmacogenetic (measured as polygenic risk scores) and epigenetic data together with clinical, sociodemographic, environmental, and neuroanatomical data. To do this, the FarmaPRED-PEP project will use data from two already recruited cohorts: the PEPS cohort from the "Genotype-Phenotype Interaction and Environment. Application to a Predictive Model in First Psychotic Episodes" study (the PEPs study from the Spanish abbreviation) (N=335) and the PAFIP cohort from "Clinical Program on Early Phases of Psychosis" (PAFIP from the Spanish abbreviation) (N = 350). These cohorts will be used to create the predictor, which will then be validated in a new cohort, the FarmaPRED cohort (N = 300). The FarmaPRED-PEP project has been designed to overcome several of the limitations identified in pharmacogenetic studies in psychiatry: (1) the sample size; (2) the phenotype heterogeneity and its definition; (3) the complexity of the phenotype and (4) the gender perspective. The global reach of the FarmaPRED-PEP project is to facilitate the effective deployment of precision medicine in national health systems.