Phenomics & Genomics of Clozapine Pharmacotherapy - Current Users

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. This is clinically relevant, because if we can
identify whether SCZ patients are more severe patients immediately, we can
start giving them clozapine as the first antipsychotic treatment. This might
result in better outcomes, since every relapse a SCZ experiences, worsens the
symptoms of this patient.

Primary:
To assess whether the genetic architecture of this severe SCZ phenotype differs
from the broad DSM-based SCZ phenotype.
To predict response and side effects after clozapine intake

Secondary:
1. To detect genetic associations with the current severe SCZ phenotype by
performing a case-control comparison with healthy participants
2. To investigate whether CLZ use increases or decreases the risk of
cardiovascular disease and early death.

This is a partly cross-sectional 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.

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 there is only a 5 minute interview with
their treating physician. A minority of patients on clozapine doesn*t have
their blood routinely monitored. These subjects will be asked to allow a single
blood draw, as well as the stopped users. 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 or in the event of syncope and insufficient blood is
obtained, we will give the participant the option to terminate his/her
participation.