Aims

CRESTAR aimed at developing tools to predict
  • who does NOT respond to usual antipsychotics, indicating treatment with clozapine as early as possible,
  • the 1% of patients who 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.
  • patients likely to be non-responders to all antipsychotics, i.e. extreme TRS, so that they can be stratified in clinical trials.

Treatment resistant schizophrenia (TRS) is one of the most disabling of all psychiatric illnesses, affecting about a third of patients with this illness (~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 up to half of TRS patients are also resistant to clozapine. Antipsychotics such as clozapine also cause side affects (adverse drug reactions), some of which are severe. CRESTAR was an SME-driven project, which focused on the development of pharmacogenomics biomarkers for schizophrenia treatment response and medication side-effects.

 

Methods

CRESTAR addressed the research question 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. CRESTAR used data from clozapine therapeutic drug monitoring and linked National population medical and pharmacy databases, alongside existing European projects (e.g. PSYCNV www.psych-cnv.eu, OPTIMISE www.optimisetrial.eu and EU-GEI www.eu-gei.eu) national initiatives (e.g. UK10K genome sequencing in schizophrenia www.uk10k.org) to identify predictive factors. In parallel CRESTAR performed health economic research on potential benefits, and ethics and patient-centered research with stakeholders.