Phenomics and Genomics of Clozapine Pharmacotherapy

NCT03253367 | Unknown DMC

• 1 other identifier: ABR: 52726 & 52728
• Study Type: observational
• Target: 2,500
• Locations: 4 countries
• Sites: 11

Brief Summary

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.

Conditions

Schizophrenia Spectrum and Other Psychotic Disorders

Keywords

Schizophrenia Spectrum and Other Psychotic Disorders

Outcome Measures

Primary Outcomes (3)

• Predict clozapine response.

  To predict clozapine response based on phenotypic information from our questionnaire (CGI + CRES) and genetic information from GWAS

  2016-2021

• Predict side effects from clozapine use

  To predict clozapine response based on phenotypic information from our questionnaire (LUNSERS) and genetic information from GWAS

  2016-2021

• Assess differences in genetic architecture (GWAS)

  To assess whether the genetic architecture of this severe SCZ phenotype differs from the broad DSM-based SCZ phenotype. this will be done by comparing the gentic material of clozapine users vs. non-clozapine users. Only the clozapine DNA has to be collected yet.

  2016-2021

Secondary Outcomes (2)

• Detect genetic associations (GWAS) Detect genetic associations current severe SCZ phenotype

  2016-2021

• Increase or decrease cardiovascular disease?

  2016-2031

Study Arms (2)

Current/former clozapine users

This group has only one visit.

Other: Blood is obtained, mostly during routine venipuncture

New clozapine users

This group will be followed for 6 months prospectively.

Other: Blood is obtained, mostly during routine venipuncture

Interventions

Blood is obtained, mostly during routine venipuncture OTHER

Current/former clozapine users; New clozapine users

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

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 13,000 healthy control subjects for whom genotype data are available in-house.

You may qualify if:

• 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

You may not qualify if:

• admission to a psychiatric unit involuntarily (not all countries)
• a history of Parkinson's disease

Sponsors & Collaborators

• Jurjen Luykx: lead

Study Sites (11)

Medical University Innsbruck

Innsbruck, 6020, Austria

RECRUITING

Niuvanniemen hospital

Kuopio, 70240, Finland

RECRUITING

LMU Munich

München, Munich, 80336, Germany

RECRUITING

Charité Universitätsmedizin Berlin

Berlin, 10117, Germany

RECRUITING

Vincent van Gogh Institute

Venray, Limburg, 5803 AC, Netherlands

WITHDRAWN

Reinier van Arkel

's-Hertogenbosch, North Brabant, 5211 LJ, Netherlands

RECRUITING

GGZ-NHN

Heerhugowaard, North Holland, 1703 WC, Netherlands

TERMINATED

GGZ Rivierduinen

Leiden, Oegstgeest, 2342 EJ, Netherlands

ENROLLING BY INVITATION

Yulius

Barendrecht, South Holland, 2994 GC, Netherlands

TERMINATED

UMC Utrecht

Utrecht, 3508 GA, Netherlands

RECRUITING

Altrecht

Utrecht, 3512 PK, Netherlands

TERMINATED

Related Links

• Website CLOZIN study

Biospecimen

Retention: SAMPLES WITH DNA

For current and former users we obtain DNA and for new users we also obtain RNA

MeSH Terms

Conditions

Schizophrenia Spectrum and Other Psychotic Disorders

Condition Hierarchy (Ancestors)

Mental Disorders

Central Study Contacts

Marte van der Horst, Drs.

CONTACT

0887551460; mzvanderhorst@gmail.com

Jurjen Luykx, PhD

CONTACT

0887568638; j.luykx@umcutrecht.nl

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: OTHER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor

Study Record Dates

• First Submitted: May 29, 2017
• First Posted: August 17, 2017
• Study Start: January 19, 2016
• Primary Completion: December 1, 2021
• Study Completion: December 1, 2021
• Last Updated: March 5, 2020

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will share

Locations

AU (1); NL (7); FI (1); DE (2)