Use of translational pharmacodynamic biomarkers in early-phase clinical studies for schizophrenia.

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Biomarkers in medicine, ISSN: 1752-0371, Vol: 8, Issue: 1, Page: 29-49

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English, Brett A; Thomas, Kelan; Johnstone, Jack; Bazih, Adam; Gertsik, Lev; Ereshefsky, Larry
Future Medicine Ltd; Future Medicine Ltd London, UK
Pharmacology, Toxicology and Pharmaceutics; Biochemistry, Genetics and Molecular Biology; Medicine
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Schizophrenia is a severe mental disorder characterized by cognitive deficits, and positive and negative symptoms. The development of effective pharmacological compounds for the treatment of schizophrenia has proven challenging and costly, with many compounds failing during clinical trials. Many failures occur due to disease heterogeneity and lack of predictive preclinical models and biomarkers that readily translate to humans during early characterization of novel antipsychotic compounds. Traditional early-phase trials consist of single- or multiple-dose designs aimed at determining the safety and tolerability of an investigational compound in healthy volunteers. However, by incorporating a translational approach employing methodologies derived from preclinical studies, such as EEG measures and imaging, into the traditional Phase I program, critical information regarding a compound's dose-response effects on pharmacodynamic biomarkers can be acquired. Furthermore, combined with the use of patients with stable schizophrenia in early-phase clinical trials, significant 'de-risking' and more confident 'go/no-go' decisions are possible.