CRESTAR

Pharmacogenomic biomarkers as clinical decision making tools for clozapine treatment of schizophrenia

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 Obiettivo del progetto (Objective)

'Treatment resistant schizophrenia (TRS) is the most disabling of all psychiatric illnesses, affecting about 1/3 of patients (~1 million Europeans), a considerable economic and social burden. First-line treatments include atypical (e.g. olanzapine) and typical (e.g. haloperidol) antipsychotics. The original atypical, clozapine, is a final option, and although it is the only antipsychotic shown to be effective in TRS, about half of TRS patients are also resistant to clozapine. CRESTAR is an SME-driven projected, focusing on the development of pharmacogenomic biomarkers for schizophrenia. It aims to develop tools to predict i) who will NOT respond to usual antipsychotics, indicating treatment with clozapine as early as possible, ii) the 1% of patients who will develop potentially fatal side effects, agranulocytosis, which is the main factor limiting clozapine use, and diabetic ketoacidosis, occurring in up to 2% of patients, and often fatal. We will also predict patients likely to be non-responders to all antipsychotics, i.e. extreme TRS, so that they can be stratified in clinical trials. CRESTAR will address these questions by examining genome-wide association data, genome sequence, epigenetic biomarkers and epidemiological data in European patient cohorts characterized for treatment response, and adverse drug reaction using data from clozapine therapeutic drug monitoring and linked National population medical and pharmacy databases, alongside existing European projects (e.g. PSYCNVs and EU-GEI) national initiatives (e.g. UK10K genome sequencing) to identify predictive factors. In parallel CRESTAR will perform health economic research on potential benefits, and ethics and patient-centered research with stakeholders. The outcome of CRESTAR will be a genomic test and associated clinical decision making tools, designed to improve pharmacological treatment of schizophrenia in both efficacy and safety, piloted with existing and new clinical trials such as OPTiMiSE.'

Introduzione (Teaser)

Schizophrenia is a debilitating mental illness. EU-funded scientists are developing biomarkers and predictive tests to identify particularly difficult cases early for faster access to the only anti-psychotic that can help.

Descrizione progetto (Article)

A disconcerting third of schizophrenia patients exhibit treatment-resistant schizophrenia (TRS), with up to half of these not responding to any medication. The rest respond only to clozapine, the original atypical anti-psychotic treatment. The earlier the drug is administered, the better the outcome.

The project http://www.crestar-project.eu/ (CRESTAR) (Pharmacogenomic biomarkers as clinical decision-making tools for clozapine treatment of schizophrenia) is exploiting genetics, epigenetics and epidemiological data from patients characterised for treatment response and adverse drug reaction. This approach should help identify patients' refractory to anti-psychotics and those who will develop potentially fatal side-effects from clozapine, particularly worrisome in children and adolescents. The patients most likely to be non-responders to all anti-psychotics were also recorded.

To date, scientists have TRS genotyped some 16 500 patients being treated with clozapine. Integrated analysis across Europe with clinical data, including epidemiological data from the Danish National Registry accelerated the discovery of genetic factors and biomarkers influencing clozapine consumption in schizophrenia patients.

The data has been used to develop a commercially viable array-based pharmacogenetic test for clozapine effects, CLOZACHIP. The researchers have now defined algorithms and are developing the parameters for use in cost-effective risk prediction. This will reduce the economic cost of treatment and improve quality of life for the patient.

Investigators have also defined TRS phenotypes and genotypes in schizophrenia populations and are working toward determining genetic associations and the causes of TRS. The analysis is poised to be complete in the next and final project period.

The researchers expect to be in a positon in the final phase to translate biomarker data analysis into the clinical arena. Such evidence-based guide on the use and monitoring of antipsychotic drugs, particularly clozapine promises to improve drug function and increase longevity for patients with TRS.

CRESTAR deliverables will reduce the need for hospitalisation, lower costs of trials and the economic impact on health systems while increasing safety and success record of clinical tests. Dissemination through the http://www.crestar-project.eu/ (project website), workshops and publications will also help to reduce any social stigma associated with schizophrenia.