A genetic and pharmacogenetic study of clozapine in schizophrenia

Treatment-resistant schizophrenia is diagnosed after unsuccessful trials of two or more antipsychotics. Clozapine has demonstrated efficacy in treatment-resistant patients but requires extensive monitoring to attain therapeutic plasma concentrations and prevent adverse effects. As a result, there is great clinical demand for characterization of intra-individual and population level variation in the progression of weight gain and for the attainment of therapeutically active clozapine plasma concentrations. Identifying such factors could stratify patients into homogeneous groups to receive targeted treatment interventions to improve patient adherence and prevent the risk of relapse or toxicity related adverse events. This thesis utilizes two cohorts; a clinical trial population of individuals with psychosis on a variety of medications and a large UK-based cohort of clozapine treated patients derived from therapeutic monitoring records. These cohorts are used to explore the contributory factors to psychotropic medication induced weight gain, with a focus on gene expression, genetics, and clinical factors. Using a variety of modelling approaches, this thesis identified associations between demographic factors and antipsychotic induced weight gain, and proposes a profile of individuals most at risk of antipsychotic weight gain. The factors influencing clozapine plasma concentrations are also outlined.