Phenomics and Genomics of Clozapine Pharmacotherapy
Phenomics and Genomics of Clozapine Pharmacotherapy
A burgeoning body of research has pointed to increased efficacy of clozapine (CLZ) over other
 antipsychotics in schizophrenia (SCZ). On the other hand, safety concerns likely cause
 underutilization across a range of European and other nations. The lack of data available to
 predict efficacy and adverse drug reactions (ADRs) of CLZ further contributes to
 underprescription rates in these countries. Here, we hypothesize that (epi)genetic and
 non-genetic factors aid to help predict treatment outcome (efficacy + ADRs) to CLZ. We
 furthermore posit that such prediction will result in enhanced quality of life of both
 patients and family members. Our primary objective is to predict CLZ treatment outcome based
 on phenotypic and genetic data obtained through the current design. The first secondary
 objective is to investigate which methylation levels/patterns are correlated with CLZ
 treatment outcome. The second secondary objective is to aid in the further elucidation of the
 genetic architecture of SCZ and any possible differences between 'regular' SCZ patients and
 those on CLZ, who are generally more severely ill. We thus intend to cover two currently
 unmet needs using a precision medicine approach: the lack of knowledge about determinants of
 treatment response to CLZ and the lack of insight into neurobiological differences between
 'regular' SCZ and relatively treatment resistant subjects (CLZ users). The prime analysis
 will be a common variant hypothesis-generating genotyping endeavor investigating treatment
 response to CLZ. Additional analyses include whole-genome methylation and gene expression
 analyses and analyses of non-genetic determinants of response. We will include 2,500 CLZ
 treated patients for our discovery cohort, which is in line with previous whole-genome
 pharmacogenomics studies and our power calculations. We will replicate any genome-wide loci
 using our prospectively collected cohort of new users (N=59). Potential yields include a
 publicly available prediction tool to help identify patients responsive to CLZ in early
 disease stages and prevent harmful effects. In addition, common variant analyses compounded
 by pathway analyses may help elucidate the mechanisms of action of CLZ. We ask for broad
 informed consent from participants ensuring rich, longitudinal phenotypic and genotypic data
 resources for both currently planned and future analyses, allowing e.g. next-generation
 sequencing focused on both CLZ and SCZ disease genetics (e.g. in large consortia). We plan to
 also generate polygenic risk scores (PRS) of CLZ efficacy and use those to identify other
 diseases or patients for which CLZ may be helpful, e.g. schizoaffective disorder patients who
 are sometimes first treated with mood stabilizers. Last, evidence hints that disparaging
 genetic loci influence efficacy to different antipsychotics. Adding genetic data from our
 cohort to existing datasets of response to other antipsychotics may help identify such loci.
 Finally, comparison studies with non-CLZ using patients suffering from SCZ may deepen the
 understanding of biological mechanisms underlying treatment resistance (or: a relatively
 severe course of illness).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.
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.
Inclusion Criteria:

 -  he/she currently uses CLZ or he/she has used CLZ in the past/will use CLZ

 -  he/she has received a diagnosis of schizophrenia, schizophreniform disorder,
 schizoaffective disorder or psychotic disorder NOS.

 -  his/her age must be ≥18 years old

 -  he/she must be able to speak and read the language of the Informed Consent (differs
 per country)

 -  he/she must be mentally competent and have decisional capacity with regard to a
 decision to participate in the current study

 Exclusion Criteria:

 -  admission to a psychiatric unit involuntarily (not all countries)

 -  a history of Parkinson's disease