Better prognosis for schizophrenia treatment
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 antipsychotic treatment. The earlier the drug is administered, the better the outcome. The project CRESTAR (Pharmacogenomic biomarkers as clinical decision making tools for clozapine treatment of schizophrenia) has exploited genetics, epigenetics and epidemiological data from patients characterised for treatment response and adverse drug reaction. This approach should help identify patients' refractory to antipsychotics 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 antipsychotics were also recorded. Scientists used genome-wide association analysis in more than 11 000 TRS patients and almost 25 000 controls. They identified 10 new genetic loci associated with TRS, and clozapine treatment failure. Integrated analysis of a 544-strong cohort accelerated the discovery of genetic factors and biomarkers to predict the effects of clozapine consumption in schizophrenia patients, particularly agranulocytosis. Investigators have also defined TRS phenotypes and genotypes in schizophrenia populations and are working toward determining genetic associations. Type 2 diabetes, prevalent in patients on clozapine, is modulated by weight gain and patients with a high polygenic risk score for schizophrenia were more likely to be receiving clozapine and be non-responders. A large body of data has set the stage and will continue to contribute value to the development of predictive tests for clozapine treatment and safety. It is anticipated that these tests will be developed based on project data and additional information that accrues in the coming years. CRESTAR deliverables could reduce the need for hospitalisation and lower costs of trials and the economic impact on health systems while increasing safety and success of clinical tests. Dissemination through the project website, workshops and publications will also help to reduce any social stigma associated with schizophrenia.
Keywords
Schizophrenia, biomarkers, antipsychotic, CRESTAR, clozapine
