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Tytuł pozycji:

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

Tytuł :
Toward Predicting Impact of Common Genetic Variants on Schizophrenia Clinical Responses With Antipsychotics: A Quantitative System Pharmacology Study
Autorzy :
Athan Spiros
Hugo Geerts
Pokaż więcej
Temat :
pharmacodynamics
system pharmacology
dopamine – physiology
serotonin physiology
cognition
motor symptom
Neurosciences. Biological psychiatry. Neuropsychiatry
RC321-571
Źródło :
Frontiers in Neuroscience, Vol 15 (2021)
Wydawca :
Frontiers Media S.A., 2021.
Rok publikacji :
2021
Kolekcja :
LCC:Neurosciences. Biological psychiatry. Neuropsychiatry
Typ dokumentu :
article
Opis pliku :
electronic resource
Język :
English
ISSN :
1662-453X
Relacje :
https://www.frontiersin.org/articles/10.3389/fnins.2021.738903/full; https://doaj.org/toc/1662-453X
DOI :
10.3389/fnins.2021.738903
Dostęp URL :
https://doaj.org/article/6dec646e7c1746408221f5ad361ef02f
Numer akcesji :
edsdoj.6dec646e7c1746408221f5ad361ef02f
Czasopismo naukowe
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-HTTLPR rs25531. The A2A2 genotype improved efficacy for all drugs, with a more complex outcome for the 5-HTTLPR rs25531 genotype. Maximal range in PANSS Total for all 27 individual combinations is 3 (aripiprazole) to 5 points (clozapine). The 5-HTTLPR L/L with aripiprazole and risperidone and the D2DRTaq1A2A2 allele with haloperidol, clozapine and quetiapine reduce the motor side-effects with opposite effects for the s/s genotype. The COMT genotype has a limited effect on antipsychotic effect and EPS. For cognition, the COMT MM 5-HTTLPR L/L genotype combination has the best performance for all antipsychotics, except clozapine. Maximal difference is 25% of the total dynamic range in a 2-back working memory task. Aripiprazole is the medication that is best suited for the largest number of genotype combinations (10) followed by Clozapine and risperidone (6), haloperidol and olanzapine (3) and quetiapine and paliperidone for one genotype. In principle, the platform could identify the best antipsychotic treatment balancing efficacy and side-effects for a specific individual genotype. Once the predictions of this platform are validated in a clinical setting the platform has potential to support rational personalized treatment guidance in clinical practice.

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