Psychotic and behavioral symptoms are common in patients with
dementia. Thus, it is rational to assume that patients with
dementia would gain benefit from combination
therapy of an
antipsychotic agent and a
cognitive enhancer.
Antipsychotics are not approved by the US FDA in elderly patients with
dementia but their use is still prevalent in other population. In the current study, we investigate the effect of atypical
antipsychotics on
acetylcholine modulation by
donepezil. In addition, the plasma pharmacokinetics on concurrent administration of these drugs was studied.
Acetylcholine modulation was carried out in the ventral hippocampus of Sprague-Dawley rats using brain microdialysis technique. In a parallel group of animals, pharmacokinetic parameters were evaluated on administration of
donepezil (5.0 mg kg(-1), ip) alone and in combination with
olanzapine,
clozapine, or
quetiapine.
Donepezil produced 348% increase in hippocampal
acetylcholine levels. Coadministration of
olanzapine and
donepezil produced 393% increase in extracellular
acetylcholine, and the effect was supported by a significantly (p < 0.05) decreased clearance of
donepezil in plasma. Whereas, other plasma pharmacokinetic parameters of
donepezil "AUC(0-24h), T (1/2) and T (max)" were moderately altered after this combination treatment. Concurrent administrations of
clozapine or
quetiapine with
donepezil produced a non-significant change in
acetylcholine levels in comparison to
donepezil alone. The plasma pharmacokinetics of
donepezil was unaltered. Results from this preclinical investigation indicate that extrapyramidal side effects may precipitate upon coadministration of
donepezil with
olanzapine. Care must be exercised by physicians and caregivers while administering these two drugs together.