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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

Simulated clinical outcome (% correct responses in a 2-Back working memory test) for the combination of memantine and cholinomimetics (donepezil and galantamine) as augmentation therapy with olanzapine in non-smoking conditions. The dose-response of memantine, memantine + donepezil (two doses) and memantine + galantamine (three doses) are fitted with a linear trendline. The slope of the memantine dose-response clearly increases when adding donepezil and galantamine in a dose-dependent way (i.e., with higher donepezil or galantamine doses), suggesting a synergistic effect.
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Figure 4: Simulated clinical outcome (% correct responses in a 2-Back working memory test) for the combination of memantine and cholinomimetics (donepezil and galantamine) as augmentation therapy with olanzapine in non-smoking conditions. The dose-response of memantine, memantine + donepezil (two doses) and memantine + galantamine (three doses) are fitted with a linear trendline. The slope of the memantine dose-response clearly increases when adding donepezil and galantamine in a dose-dependent way (i.e., with higher donepezil or galantamine doses), suggesting a synergistic effect.

Mentions: Figure 4 shows a dose-response of memantine on cognitive effects in the presence of olanzapine, and with donepezil or galantamine. Memantine increases cognitive effects dose-dependently in the absence of the AChE-I and the slope (in % correct on the 2-back WM test for 0–40 mg of memantine) of 0.08 is increased to 0.23 and 0.34 when adding donepezil 5 and 10 mg, respectively. When adding galantamine, the slope is increased to 0.13, 0.30, and 0.16 for 8, 16, and 24 mg, respectively. This suggests a synergistic effect with increasing concentrations of donepezil and galantamine, although at the highest galantamine dose of 24 mg the effect is somewhat attenuated. This synergistic effect with olanzapine however disappears in the smoking conditions.


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)

Simulated clinical outcome (% correct responses in a 2-Back working memory test) for the combination of memantine and cholinomimetics (donepezil and galantamine) as augmentation therapy with olanzapine in non-smoking conditions. The dose-response of memantine, memantine + donepezil (two doses) and memantine + galantamine (three doses) are fitted with a linear trendline. The slope of the memantine dose-response clearly increases when adding donepezil and galantamine in a dose-dependent way (i.e., with higher donepezil or galantamine doses), suggesting a synergistic effect.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Simulated clinical outcome (% correct responses in a 2-Back working memory test) for the combination of memantine and cholinomimetics (donepezil and galantamine) as augmentation therapy with olanzapine in non-smoking conditions. The dose-response of memantine, memantine + donepezil (two doses) and memantine + galantamine (three doses) are fitted with a linear trendline. The slope of the memantine dose-response clearly increases when adding donepezil and galantamine in a dose-dependent way (i.e., with higher donepezil or galantamine doses), suggesting a synergistic effect.
Mentions: Figure 4 shows a dose-response of memantine on cognitive effects in the presence of olanzapine, and with donepezil or galantamine. Memantine increases cognitive effects dose-dependently in the absence of the AChE-I and the slope (in % correct on the 2-back WM test for 0–40 mg of memantine) of 0.08 is increased to 0.23 and 0.34 when adding donepezil 5 and 10 mg, respectively. When adding galantamine, the slope is increased to 0.13, 0.30, and 0.16 for 8, 16, and 24 mg, respectively. This suggests a synergistic effect with increasing concentrations of donepezil and galantamine, although at the highest galantamine dose of 24 mg the effect is somewhat attenuated. This synergistic effect with olanzapine however disappears in the smoking conditions.

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