Phenomics and Genomics of Clozapine Pharmacotherapy

Rationale Clozapine (CLZ) is generally prescribed if at least two trials of antipsychotic agents have not led to satisfactory clinical improvement, thereby implying that patients on CLZ generally suffer from more severe and/or persistent symptoms than patients suffering from schizophrenia spectrum disorders (SCZ) on other antipsychotic agents. Unraveling the (functional) genetic variation underlying this severe SCZ phenotype therefore has the potential to deepen our understanding of the biological underpinnings of SCZ beyond the boundaries of DSM-based consensus criteria. Such knowledge in turn has the potential to shape future pharmacotherapeutic research. The investigators here hypothesize that targeting this phenotype in genome-wide association studies and next-generation sequencing studies will signal genetic risk loci implicated in this severe SCZ phenotype. In the future, this may lead to early detection of severe SCZ, which in turn will enable tailoring of pharmacotherapeutic strategies to such SCZ subtypes. The results of this genetic part of the study will be combined with the results from our other research protocol ('Phenomics and genomic of clozapine pharmacotherapy - New Users').The overarching goal of both projects is to create a prediction model for clozapine outcome (response (and side effects). This model includes genetic, epigenetic and clinical data. Objectives Primary: 1\) To predict CLZ efficacy and ADRs (=treatment outcome) based on phenotypic and genetic data obtained in this study. Secondary: 1. To investigate which non-genetic factors, methylation and gene expression levels/patterns predict treatment outcome after initiating CLZ; 2. As the genetic architecture of SCZ has not been fully elucidated, the current project will aid in the further elucidation of the genetic architecture of SCZ and any possible differences between 'regular' SCZ patients (those not considered treatment resistant) and those on CLZ (considered generally to be a more homogeneous and severe group). Study design This is a mostly cross-sectional study, in which both phenotypic and genotypic data are gathered from this study population that currently uses CLZ or has used CLZ in the past. A genome-wide association study (GWAS) will be performed to reveal possible differences in genetic architecture between patients who use or have used CLZ and the broad schizophrenia phenotype on the one hand and between those who use or have used CLZ and healthy controls on the other. Targeted next-generation sequencing may be used to follow-up possible positive associations. The genetic data will be used to analyse which genetic variants are associated with CLZ response and/or side effects. Study population The investigators will include 2,500 patients diagnosed with schizophrenia, schizophreniform disorder, schizoaffective disorder or psychotic disorder NOS (together referred to as SCZ) \>18 years of age who are currently on CLZ treatment or have used CLZ in the past. Publicly available Psychiatric Genomics Consortium (PGC) GWAS data will be used for comparisons with the broad schizophrenia phenotype group. For the purpose of the case-control comparison, the 2,500 subjects who use or have used CLZ will be age and sex-matched to 30,000 healthy control subjects for whom genotype data are available in-house. Intervention No intervention will be applied. Main study parameters/endpoints 1. To assess whether the genetic architecture of this severe SCZ phenotype differs from the broad DSM-based SCZ phenotype. 2. To predict clozapine response and side effects based on phenotypic and genetic data obtained in this study. Nature and extent of the burden and risks associated with participation, benefit and group relatedness Almost all patients on CLZ regularly have their blood drawn for routine white blood cell counts and/or CLZ blood level assessments. The investigators anticipate that the majority of the study population will consist of such patients as white blood cell monitoring is strictly enforced in clinical practice for this patient group. For these patients, no additional risks will be attached to the study, as the blood necessary for DNA extraction for the current study will be drawn during these routinely performed venipunctures. Time investment will also be low as the patients will only undergo a 10-minute interview. A minority of patients on CLZ does not have their blood routinely monitored and neither do patients who have used CLZ in the past. These subjects will be asked to allow a single blood draw. A venipuncture entails the risk of a hematoma (blood leaving the vessel). The investigators aim to minimize this risk by only allowing experienced personnel to draw blood and in the event of deeply located or thin veins request central lab personnel to perform the venipuncture. Although a hematoma resulting from a traumatic puncture imposes an esthetical burden on the subject, no serious health risks are involved.