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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 various cholinomimetics (donepezil and galantamine) with different antipsychotics in non-smoking schizophrenia patients (A) and in smoking schizophrenia patients (B). Both galantamine and donepezil show a dose-dependent improvement in the presence of risperidone, aripiprazole, and haloperidol, although the effect sizes differ. However, there is no improvement for quetiapine, probably due to the high baseline, and a more complex dose-response for olanzapine. Smoking tends to slightly enhance the responses of cognition in augmentation therapy with risperidone and haloperidol. However, smoking also tends to slightly decrease the responses of cognition in augmentation therapy with quetiapine and olanzapine. This is probably due to the many non-linear interactions between cholinergic modulation and the complex pharmacodynamics of antipsychotics.
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Figure 3: Simulated clinical outcome (% correct responses in a 2-Back working memory test) for the combination of various cholinomimetics (donepezil and galantamine) with different antipsychotics in non-smoking schizophrenia patients (A) and in smoking schizophrenia patients (B). Both galantamine and donepezil show a dose-dependent improvement in the presence of risperidone, aripiprazole, and haloperidol, although the effect sizes differ. However, there is no improvement for quetiapine, probably due to the high baseline, and a more complex dose-response for olanzapine. Smoking tends to slightly enhance the responses of cognition in augmentation therapy with risperidone and haloperidol. However, smoking also tends to slightly decrease the responses of cognition in augmentation therapy with quetiapine and olanzapine. This is probably due to the many non-linear interactions between cholinergic modulation and the complex pharmacodynamics of antipsychotics.

Mentions: We then simulated the effect of augmentation strategy with ACh inhibitors added to antipsychotics on cognitive outcome (Figure 3), both in the absence and presence of nicotine. In non-smokers, AChE-I dose-dependently improved cognitive outcomes with risperidone, aripiprazole (donepezil only) and haloperidol, with only the 24 mg galantamine showing a robust improvement of >10% in correct responses. In the presence of olanzapine and aripiprazole with galantamine, a tendency was observed for an inverse U-shape dose-response. In the presence of quetiapine, increased AChE-I worsened responses.


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 various cholinomimetics (donepezil and galantamine) with different antipsychotics in non-smoking schizophrenia patients (A) and in smoking schizophrenia patients (B). Both galantamine and donepezil show a dose-dependent improvement in the presence of risperidone, aripiprazole, and haloperidol, although the effect sizes differ. However, there is no improvement for quetiapine, probably due to the high baseline, and a more complex dose-response for olanzapine. Smoking tends to slightly enhance the responses of cognition in augmentation therapy with risperidone and haloperidol. However, smoking also tends to slightly decrease the responses of cognition in augmentation therapy with quetiapine and olanzapine. This is probably due to the many non-linear interactions between cholinergic modulation and the complex pharmacodynamics of antipsychotics.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Simulated clinical outcome (% correct responses in a 2-Back working memory test) for the combination of various cholinomimetics (donepezil and galantamine) with different antipsychotics in non-smoking schizophrenia patients (A) and in smoking schizophrenia patients (B). Both galantamine and donepezil show a dose-dependent improvement in the presence of risperidone, aripiprazole, and haloperidol, although the effect sizes differ. However, there is no improvement for quetiapine, probably due to the high baseline, and a more complex dose-response for olanzapine. Smoking tends to slightly enhance the responses of cognition in augmentation therapy with risperidone and haloperidol. However, smoking also tends to slightly decrease the responses of cognition in augmentation therapy with quetiapine and olanzapine. This is probably due to the many non-linear interactions between cholinergic modulation and the complex pharmacodynamics of antipsychotics.
Mentions: We then simulated the effect of augmentation strategy with ACh inhibitors added to antipsychotics on cognitive outcome (Figure 3), both in the absence and presence of nicotine. In non-smokers, AChE-I dose-dependently improved cognitive outcomes with risperidone, aripiprazole (donepezil only) and haloperidol, with only the 24 mg galantamine showing a robust improvement of >10% in correct responses. In the presence of olanzapine and aripiprazole with galantamine, a tendency was observed for an inverse U-shape dose-response. In the presence of quetiapine, increased AChE-I worsened responses.

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