psychosis psychotic disorders
Conditions
Interventions
adverse reactions
clozapine
efficacy
genetics
Sponsors
Universitair Medisch Centrum Utrecht
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: -he/she currently uses clozapine or is about to initiate a treatment of clozapine -he/she has received a diagnosis of schizophrenia or schizoaffective disorder, either clinician-rated based on DSM-IV or 5 criteria or according to a (semi-)structured interview -his/her age must be >=18 years old -he/she must be able to speak and read the Dutch language -he/she must understand the information provided about the study and express a willingness to participate
Exclusion criteria
Exclusion criteria: - admission to a psychiatric unit involuntarily in the context of an *inbewaringstelling* (IBS) or *rechterlijke machtiging* (RM)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| In a discovery cohort a case-control genome-wide association study (GWAS) will be performed on 2000 clozapine using subjects (cases) and >30,000 already available SCZ patients (controls, drawn from the most recent Psychiatric Genomics Consortium analysis, http://www.med.unc.edu/pgc/downloads). We hereby aim to reveal potential differences in the genetic architecture between the severe CLZ-SCZ phenotype and the broad SCZ phenotype. This analysis will be compounded by polygenic risk score analyses determining explained variances by risk loci at predefined p-value association cut-offs of 10-7, 10-6, 10-5, 10-4, 10-3, 10-2, 0.05, 0.1 and 0.5 between the CLZ-SCZ phenotype and the broad SCZ phenotype. | — |
Secondary
| Measure | Time frame |
|---|---|
| Second, by running a case-control GWAS for the CLZ-SCZ phenotype as cases and healthy subjects as controls (13,000 already available healthy individuals who will be age and sex-matched, i.e. a group of healthy controls drawn from a genetic study of amyotrophic lateral sclerosis) we test our hypothesis that stronger genetic associations may be detected when using this homogeneous, severe psychiatric phenotype compared with broad behavioral phenotypes. This analysis will be compounded by polygenic risk score analyses determining explained variances by risk loci at predefined p-value association cut-offs of 10-7, 10-6, 10-5, 10-4, 10-3, 10-2, 0.05, 0.1 and 0.5 between the CLZ-SCZ phenotype and the healthy controls. Third, a replication cohort of the same size as the discovery cohort (N=2000 clozapine using subjects and the same number of healthy controls) will be used to replicate any positive associations for each of the two GWAS analyses. Fourth, positive associations in or near genes will be followed up by targeted sequencing of one or more of these genes using the Illumina MiSeq next-generation sequencing machine available at our facility or a different next-generation sequencing (NGS) machine. Fifth, we will additionally perform whole-exome sequencing on the subjects who suffered from any of the aforementioned serious ADRs during clozapine use and compare these results to patients who have used clozapine for over 4 years and have been free of this ADR. Sixth, in subjects who start clozapine quantitative changes in methylation patterns across the genome will be correlated with response to clozapine and the occurrence of the abovementioned three adverse drug reactions. Seventh, to dissect the phenotypic characteristics determining response to clozapine and the occurrence of adverse drug reactions we will collect a range of continuous and categorical data before treatment initiation and also after treatment initiation for state-dependent info | — |
Countries
The Netherlands
Outcome results
None listed