Abstract
BackgroundCNS disorders are lagging behind other indications such as oncology in implementing genotype-dependent treatment algorithms for personalized medicine. This is due to the limited knowledge about the interaction of the relevant biology and the drug’s pharmacologyMethodsWe applied a mechanism-based computer model of a cortico-striatal-thalamocortical loop of the dorsal motor circuit that has been calibrated with clinical data on antipsychotic treatment in schizophrenia patients (Spiros, Roberts et al. 2017). The Quantitative Systems Pharmacology (QSP) model is based on the appropriate connections between basal ganglia regions and consists of 220 neurons (8 different cell types), 3500 synapses and implementations of 32 CNS active targets, based on their unique locations and coupling with intracellular pathways. COMTVal156Met, 5-HTTLPR rs 23351 s/L and D2DRTaq1A1 genotypes are implemented using human imaging data in non-medicated human volunteersResultsThe dose-dependent antipsychotic effect for risperidone, aripiprazole and paliperidone is sensitive to the COMT genotype with the MM genotype having the greatest difference with the wild-type. Interestingly the 5-HTTLPR genotype interacts with the COMT genotype: this difference is positive for 5-HTTLPRss and negative for 5-HTTLPR LL. Olanzapine, quetiapine, clozapine and haloperidol are affected much less. The D2DRTaq1A allele interacts in a complex way with the COMT genotype with haloperidol, aripiprazole and risperidone and with the 5-HTLLPR genotype for haloperidol, aripiprazole, risperidone and paliperidone. These effects are anticipated to be detectable in clinical settings.DiscussionThe QSP platform predicts strong and complex genotype-dependent interactions with aripiprazole, risperidone, haloperidol and paliperidone and to a much smaller degree with olanzapine, quetiapine and clozapine. These predictions could in principle be verified in clinical setting and could lead to rational personalized treatment guidance
Highlights
Recent Magnetic Resonance Imaging (MRI) studies on schizophrenia suggest that auditory verbal hallucinations (AVH) might be caused by alterations in connectivity of frontal and temporoparietal language-related areas.[3] as well as in connectivity of the default mode network (DMN).[1]
Tract-based spatial statistics (TBSS) allows voxel-wise analysis of multi-subject diffusion data based on fractional anisotropy (FA), assessing microstructural properties of white matter tracts
This study investigates brain white matter tracts in 85 schizophrenia patients and 111 healthy, matched controls using TBSS analysis
Summary
Schizophrenia is a highly heritable psychiatric disorder. In the past 30 years, thousands of case-control and family-designed association studies have examined candidate genes for schizophrenia. To assist the field in interpreting this large volume of gene-association studies, the online SzGene database was created and included meta analyses for 287 polymorphisms at the time of its final update in 2010. Since more than one-thousand new gene-association studies in schizophrenia
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