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-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.

Keywords: cognition; dopamine – physiology; motor symptom; pharmacodynamics; serotonin physiology; system pharmacology.

FIGURE 1

Effect of COMT, 5-HTTLPR rs25531 and D2DRTaq1 genotypes on change in PANSS total vs. placebo for the different antipsychotics at their standard doses. The figure shows the differential effects of the homozygotes (for instance MM/*/* and VV/*/*) vs. the heterozygote subjects (for instance MV/*/*). All results are averaged over the 9 possible combinations of the other two genotypes with the appropriate distribution depending upon the frequency of the genotypes. The biggest effects for the most drugs are seen with the DRD2Taq1 allele, where the */*/A2A2 genotype tends to increase clinical response for drugs with strong D₂R antagonism, but with an opposite effect for drugs with weak D₂R antagonism (clozapine and quetiapine). The effect of COMT genotype is limited, but the 5-HTT LPR genotype only has an effect with aripiprazole (*/LL/* worsens outcome) and a complex relationship with risperidone where */Ls/* has the worst outcome.

FIGURE 2

Effect of COMT, 5-HTTLPR rs25531 and D2DRTaq1 genotypes on the slope of the PANSS Total dose-response for the range of doses associated with the different antipsychotics (number of points per 100% change in dose). The figure shows the differential effects of the homozygotes (for instance MM/*/* and VV/*/*) vs. the heterozygote subjects (for instance MV/*/*). All results are averaged over the 9 possible combinations of the other two genotypes with the appropriate distribution depending upon the frequency of the genotypes. Note that positive slope changes indicate that smaller doses are better, while negative slope changes indicate that larger doses are better. Like with the effects on the change in PANSS Total, the biggest effects for the most drugs are seen with the DRD2Taq1 allele, with the */*/A2A2 genotype favorable in drugs with strong D₂R antagonism, but not in drugs with weak D₂R antagonism (clozapine and quetiapine). The effect of the COMT genotype is limited, but the 5-HTT LPR genotype has only an effect with aripiprazole and risperidone. The size of the effect is limited; however, for instance the 0.5 effect on slope for */LL/* with aripiprazole translates to a 0.5 point improvement for a dose increase of 100% of the standard dose.

FIGURE 3

Effect of COMT, 5-HTTLPR rs25531 and D2DRTaq1 genotypes on the EPS liability for the different antipsychotics. The figure shows the changes in probability for patients needing anticholinergic mediation to address their motor side-effects (for instance MM/*/* and VV/*/*) vs. the heterozygote subjects (for instance MV/*/*). All results are averaged over the 9 possible combinations of the other two genotypes with the appropriate distribution depending upon the frequency of the genotypes. While the COMT genotype has no effect on EPS liability, both the 5-HTTLPR and DRD2Taq1 alleles affect this side-effect substantially. The */LL/* genotype, by virtue of its lower 5-HT tone, acts as a 5-HT_2A antagonism mechanism; while the */*/A2A2 genotype has a higher dopamine D₂R expression which effectively acts as less D₂ antagonism.

FIGURE 4

Minimum and maximum effect of cognitive outcome on the 2-back working memory test for the different antipsychotics at the clinically most relevant dose and modulated by 9 different combinations of COMTVal158Met and 5-HTTLPR L/s genotypes. The variability can be substantial (>25 percentage points, a quart of the total dynamical range of the scale) for risperidone, paliperidone and aripiprazole.

FIGURE 5

Effect of COMT and 5-HTTLPR rs25531 genotypes on aripiprazole dose-response on simulated cognitive outcome for schizophrenia patients. Most COMTMM-5HTT patients have an essentially flat dose-response and performs quite well; in contrast for COMT VV subjects and to a lesser extent for COMTMV subjects, higher aripiprazole doses significantly improve cognitive outcome.