Toward Predicting Impact of Common Genetic Variants on Schizophrenia Clinical Responses With Antipsychotics: A Quantitative System Pharmacology Study.

ABSTRACT: CNS disorders are lagging behind other indications in implementing genotype-dependent treatment algorithms for personalized medicine. This report uses a biophysically realistic computer model of an associative and dorsal motor cortico-striatal-thalamo-cortical loop and a working memory cortical model to investigate the pharmacodynamic effects of COMTVal158Met rs4680, 5-HTTLPR rs 25531 s/L and D2DRTaq1A1 genotypes on the clinical response of 7 antipsychotics. The effect of the genotypes on dopamine and serotonin dynamics and the level of target exposure for the drugs was calibrated from PET displacement studies. The simulations suggest strong gene-gene pharmacodynamic interactions unique to each antipsychotic. For PANSS Total, the D2DRTaq1 allele has the biggest impact, followed by the 5-HT

SUBMITTER: Spiros A 

PROVIDER: S-EPMC8511786 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature