Primary:-To assess whether the genetic architecture of this severe SCZ phenotype differs from the broad DSM-based SCZ phenotypeSecondary:-To detect genetic associations with the current severe SCZ phenotype (case-control comparison)-To unravel…
ID
Source
Brief title
Condition
- Schizophrenia and other psychotic disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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 outcome
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 information. These may
be divided into epidemiological, illness-related, pharmacotherapeutic, and
other parameters (see under *Study parameters*). These data will be collected
in a subset of the study population (N=200): only patients who are about to
initiate clozapine treatment will be followed up. The collected data will be
used to try and predict which patients are more likely to benefit from
clozapine and which patients are more likely to suffer from adverse drug
reactions. A final aim of the current project is to store participants* DNA and
blood for biobanking so that their DNA and blood may be used for future
research questions, e.g. by the integration of data collected by international
consortia that collect SCZ samples for GWAS and next-generation sequencing
(such as the Psychiatric Genomics Consortium, http://www.med.unc.edu/pgc) and
immunology measurements in blood 39. For both GWAS and NGS, limited sample
sizes have precluded drawing definite conclusions regarding the neurobiological
pathways involved in SCZ and the variance explained by genetic risk loci 1, 4,
5. Considering the increase in genetic knowledge leveraged by increases in
sample sizes of SCZ GWASs 1-3 it is likely that international collaborations
will yield increased understanding of both endpoints during the course and
after termination of the CLOZ-NL study. For this purpose, DNA will be stored at
the central biobank of the UMCU only of those participants who specifically
consent to have their DNA and blood stored for such possible future analyses.
Background summary
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 clozapine generally suffer from more severe and/or persistent
symptoms than SCZ patients 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. We 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. Moreover, it is currently impossible to predict
who will respond to clozapine treatment. Genetic data may help prognosticate
which patients will benefit from clozapine treatment. Besides genotypic data, a
range of epidemiological, illness-related, pharmacotherapeutic and other
parameters may determine treatment outcome in those patients who use clozapine.
This has not been systematically investigated in prospective designs. In
addition, adverse drug reactions (ADRs) to clozapine carry a high burden of
disease and sometimes prompt non-compliance. The underpinnings of these ADRs
are poorly understood. Elucidating both the genetic and phenotypic determinants
underlying the occurrence of clozapine*s ADRs may be of direct benefit to
clinical practice because such knowledge may in the future enable tailoring of
antipsychotic treatment choices to the individual patient.
Study objective
Primary:
-To assess whether the genetic architecture of this severe SCZ phenotype
differs from the broad DSM-based SCZ phenotype
Secondary:
-To detect genetic associations with the current severe SCZ phenotype
(case-control comparison)
-To unravel genetic determinants of both response and adverse reactions to
clozapine
-To design a model that comprehensively dissects the phenotypic characteristics
predicting response and adverse drug reactions to clozapine
-To discover changes in methylation after instatement of clozapine
Study design
This is a partly cross-sectional, partly prospective study in which both
phenotypic and genotypic data are gathered from this study population that uses
clozapine. A genome-wide association study (GWAS) will be performed to reveal
possible differences in genetic architecture between patients on clozapine and
the broad schizophrenia phenotype on the one hand and between those on
clozapine and healthy controls on the other. Targeted next-generation
sequencing may be used to follow-up possible positive associations. Changes in
methylation before and after the start of clozapine will be assessed. Finally,
a range of epidemiological, illness-related, pharmacotherapeutic and other
phenotypic data will be collected before treatment initiation for a subset of
the study population. These phenotypic data will be used to try and predict
treatment outcome following clozapine initiation.
Study burden and risks
Almost all patients on clozapine regularly have their blood drawn for routine
white blood cell counts and/or clozapine blood level assessments. We 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 risks will be attached to the study as
the blood necessary for DNA extraction for the current study will be drawn from
these routinely performed venipunctures. In addition, time investment for these
participants will be negligible as only three brief questions will be asked
during a routine visit with their in or outpatient treating physician. Patients
about to initiate clozapine treatment will also undergo routine venipunctures
for the purpose of the same assessments as mentioned above. They will
additionally be asked to fill out questionnaires and allow for a brief
interview to obtain epidemiological, illness-related and pharmacotherapeutic
phenotypic data. Although the time investment of this latter group may thus be
substantial, no invasive procedures will be applied here either and we will
give every participant the possibility to opt out of these phenotypic
assessments at any moment.
A minority of patients on clozapine doesn*t have their blood routinely
monitored. These subjects will be asked to allow a single blood draw. A
venipuncture entails the risk of a hematoma (blood leaving the vessel). We 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. Should the venipuncture be traumatic and insufficient blood is
obtained, we will give the participant the option to terminate his/her
participation.
Universiteitsweg 100 Universiteitsweg 100
Utrecht 3584 CD
NL
Universiteitsweg 100 Universiteitsweg 100
Utrecht 3584 CD
NL
Listed location countries
Age
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
- admission to a psychiatric unit involuntarily in the context of an *inbewaringstelling* (IBS) or *rechterlijke machtiging* (RM)
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL52215.041.15 |