Limits...
Assessing the synergy between cholinomimetics and memantine as augmentation therapy in cognitive impairment in schizophrenia. A virtual human patient trial using quantitative systems pharmacology.

Geerts H, Roberts P, Spiros A - Front Pharmacol (2015)

Bottom Line: Smoking reduces the effect of cholinomimetics with aripiprazole and olanzapine, but enhances the effect in haloperidol and risperidone.Adding memantine to antipsychotics improves cognition except with quetiapine, an effect enhanced with smoking.Combining cholinomimetics, antipsychotics and memantine in general shows an additive effect, except for a negative interaction with aripiprazole and quetiapine and a synergistic effect with olanzapine and haloperidol in non-smokers and haloperidol in smokers.

View Article: PubMed Central - PubMed

Affiliation: In Silico Biosciences Berwyn, PA, USA ; Perelman School of Medicine, University of Pennsylvania Philadelphia, PA, USA.

ABSTRACT
While many drug discovery research programs aim to develop highly selective clinical candidates, their clinical success is limited because of the complex non-linear interactions of human brain neuronal circuits. Therefore, a rational approach for identifying appropriate synergistic multipharmacology and validating optimal target combinations is desperately needed. A mechanism-based Quantitative Systems Pharmacology (QSP) computer-based modeling platform that combines biophysically realistic preclinical neurophysiology and neuropharmacology with clinical information is a possible solution. This paper reports the application of such a model for Cognitive Impairment In Schizophrenia (CIAS), where the cholinomimetics galantamine and donepezil are combined with memantine and with different antipsychotics and smoking in a virtual human patient experiment. The results suggest that cholinomimetics added to antipsychotics have a modest effect on cognition in CIAS in non-smoking patients with haloperidol and risperidone and to a lesser extent with olanzapine and aripiprazole. Smoking reduces the effect of cholinomimetics with aripiprazole and olanzapine, but enhances the effect in haloperidol and risperidone. Adding memantine to antipsychotics improves cognition except with quetiapine, an effect enhanced with smoking. Combining cholinomimetics, antipsychotics and memantine in general shows an additive effect, except for a negative interaction with aripiprazole and quetiapine and a synergistic effect with olanzapine and haloperidol in non-smokers and haloperidol in smokers. The complex interaction of cholinomimetics with memantine, antipsychotics and smoking can be quantitatively studied using mechanism-based advanced computer modeling. QSP modeling of virtual human patients can possibly generate useful insights on the non-linear interactions of multipharmacology drugs and support complex CNS R&D projects in cognition in search of synergistic polypharmacy.

No MeSH data available.


Related in: MedlinePlus

Effect of increasing memantine dose on anticipated N-back working memory tests outcome (% correct responses in a 2-Back working memory test) in the presence of the five antipsychotics. (A) Non-smokers, (B) smokers. The simulations suggest evidence for a dose-dependent effect of memantine for all antipsychotics except quetiapine. The effect is slightly amplified for patients on nicotine. Note that the maximal dose (40 mg) is twice the regular dose used in Alzheimer patients.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4585031&req=5

Figure 2: Effect of increasing memantine dose on anticipated N-back working memory tests outcome (% correct responses in a 2-Back working memory test) in the presence of the five antipsychotics. (A) Non-smokers, (B) smokers. The simulations suggest evidence for a dose-dependent effect of memantine for all antipsychotics except quetiapine. The effect is slightly amplified for patients on nicotine. Note that the maximal dose (40 mg) is twice the regular dose used in Alzheimer patients.

Mentions: We studied the effect of increasing memantine doses on the performance of the in silico network for CIAS in the presence of antipsychotics. Figures 2A,B shows the effect of memantine on the estimated 2-back working memory outcomes, respectively in the absence and presence of nicotine. In the absence of smoking, with the exception of quetiapine, all drugs improve cognitive readout with increasing memantine doses with the greatest effect observed for aripiprazole (from 69 accuracy to 81% in a 2-back test). For smoking conditions, the increase in frequency of accurate responses as a function of the optimal memantine dose is amplified for Risperidone (maximal increase from 5 to 14%), Haloperidol (maximal effect increases from 5 to 12%) and olanzapine (maximal effect from 6 to 11%), but not for aripiprazole and quetiapine. Note that this maximal effect happens at memantine doses of 40 mg. At clinically relevant doses of 20 mg, the effect is about half as much.


Assessing the synergy between cholinomimetics and memantine as augmentation therapy in cognitive impairment in schizophrenia. A virtual human patient trial using quantitative systems pharmacology.

Geerts H, Roberts P, Spiros A - Front Pharmacol (2015)

Effect of increasing memantine dose on anticipated N-back working memory tests outcome (% correct responses in a 2-Back working memory test) in the presence of the five antipsychotics. (A) Non-smokers, (B) smokers. The simulations suggest evidence for a dose-dependent effect of memantine for all antipsychotics except quetiapine. The effect is slightly amplified for patients on nicotine. Note that the maximal dose (40 mg) is twice the regular dose used in Alzheimer patients.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585031&req=5

Figure 2: Effect of increasing memantine dose on anticipated N-back working memory tests outcome (% correct responses in a 2-Back working memory test) in the presence of the five antipsychotics. (A) Non-smokers, (B) smokers. The simulations suggest evidence for a dose-dependent effect of memantine for all antipsychotics except quetiapine. The effect is slightly amplified for patients on nicotine. Note that the maximal dose (40 mg) is twice the regular dose used in Alzheimer patients.
Mentions: We studied the effect of increasing memantine doses on the performance of the in silico network for CIAS in the presence of antipsychotics. Figures 2A,B shows the effect of memantine on the estimated 2-back working memory outcomes, respectively in the absence and presence of nicotine. In the absence of smoking, with the exception of quetiapine, all drugs improve cognitive readout with increasing memantine doses with the greatest effect observed for aripiprazole (from 69 accuracy to 81% in a 2-back test). For smoking conditions, the increase in frequency of accurate responses as a function of the optimal memantine dose is amplified for Risperidone (maximal increase from 5 to 14%), Haloperidol (maximal effect increases from 5 to 12%) and olanzapine (maximal effect from 6 to 11%), but not for aripiprazole and quetiapine. Note that this maximal effect happens at memantine doses of 40 mg. At clinically relevant doses of 20 mg, the effect is about half as much.

Bottom Line: Smoking reduces the effect of cholinomimetics with aripiprazole and olanzapine, but enhances the effect in haloperidol and risperidone.Adding memantine to antipsychotics improves cognition except with quetiapine, an effect enhanced with smoking.Combining cholinomimetics, antipsychotics and memantine in general shows an additive effect, except for a negative interaction with aripiprazole and quetiapine and a synergistic effect with olanzapine and haloperidol in non-smokers and haloperidol in smokers.

View Article: PubMed Central - PubMed

Affiliation: In Silico Biosciences Berwyn, PA, USA ; Perelman School of Medicine, University of Pennsylvania Philadelphia, PA, USA.

ABSTRACT
While many drug discovery research programs aim to develop highly selective clinical candidates, their clinical success is limited because of the complex non-linear interactions of human brain neuronal circuits. Therefore, a rational approach for identifying appropriate synergistic multipharmacology and validating optimal target combinations is desperately needed. A mechanism-based Quantitative Systems Pharmacology (QSP) computer-based modeling platform that combines biophysically realistic preclinical neurophysiology and neuropharmacology with clinical information is a possible solution. This paper reports the application of such a model for Cognitive Impairment In Schizophrenia (CIAS), where the cholinomimetics galantamine and donepezil are combined with memantine and with different antipsychotics and smoking in a virtual human patient experiment. The results suggest that cholinomimetics added to antipsychotics have a modest effect on cognition in CIAS in non-smoking patients with haloperidol and risperidone and to a lesser extent with olanzapine and aripiprazole. Smoking reduces the effect of cholinomimetics with aripiprazole and olanzapine, but enhances the effect in haloperidol and risperidone. Adding memantine to antipsychotics improves cognition except with quetiapine, an effect enhanced with smoking. Combining cholinomimetics, antipsychotics and memantine in general shows an additive effect, except for a negative interaction with aripiprazole and quetiapine and a synergistic effect with olanzapine and haloperidol in non-smokers and haloperidol in smokers. The complex interaction of cholinomimetics with memantine, antipsychotics and smoking can be quantitatively studied using mechanism-based advanced computer modeling. QSP modeling of virtual human patients can possibly generate useful insights on the non-linear interactions of multipharmacology drugs and support complex CNS R&D projects in cognition in search of synergistic polypharmacy.

No MeSH data available.


Related in: MedlinePlus