in japan , there was no choice of medication for the treatment of alzheimer s disease ( ad ) , other than donepezil , for more than a decade , as rivastigmine , galantamine , and memantine were not approved by the japanese ministry of health , labour and welfare until 2011 .
the recent availability of the three medications is leading to a new stage in the medical treatment of ad in japan .
donepezil and galantamine block only acetylcholinesterase , while rivastigmine is a dual inhibitor of acetylcholinesterase and butyrylcholinesterase . on the other hand ,
galantamine is a potent allosteric potentiating ligand of nicotinic receptors.1 memantine blocks the n - methyl - d - aspartate receptor2 and thereby protects nerve cells from excess stimulation by glutamate .
since these drugs have different pharmacological profiles , one should select the appropriate drug carefully , according to the ad progression and symptoms of the patients . however , there are few instances of using the newly approved drugs for the treatment of ad in japan . here
, we report on two patients with ad who showed deterioration in the behavioral and psychological symptoms of dementia ( bpsd ) associated with switching to donepezil from rivastigmine after a clinical phase iii trial .
a 76-year - old woman without family history of ad presented with a 5-year history of cognitive decline and a decrease in her activities of daily living .
she needed the help of her family for daily activities such as excretion , bathing , and changing her clothes . on the mini - mental state examination ( mmse ) ,
a cranial mri revealed moderate atrophy of the cerebral cortices , an enlargement of the inferior horn of the right lateral ventricle , and a slight ischemic change in the deep white matter .
brain bloodflow scintigraphy showed a right dominant decline in the parietotemporal lobes and a decline in the posterior cingulate gyrus .
there was no use of drugs or physical or neurological factors to explain her cognitive disturbance . based on these findings
the patient participated in the clinical study of rivastigmine  a 24-week , multicenter , randomized , double - blind , placebo - controlled , parallel - group , dose - finding study evaluating the efficacy , safety , and tolerability of the once - daily rivastigmine patch formulation in patients with probable ad ( mmse score of 1020)3 and an accompanying , open - label , 52-week , extension study .
one week after the extension study with a rivastigmine patch ( 18 mg / day ) , she started treatment with donepezil at a dose of 3 mg / day .
she suffered from insomnia 3 days later and did not follow family advice , eg , walking around outside regardless of bad weather and ending up being protected by the police . in spite of it being a very hot day , she went out and lost her way , and was subsequently put under protective custody at a police station .
consequent to these occurrences , she was admitted to national hospital organization , kikuchi hospital .
her scores on the neuropsychiatric inventory ( npi ) before taking donepezil and at admission were 17 and 38 points , respectively ( figure 1a ) .
her agitation , irritability , and loitering tendencies improved after her discontinuation of donepezil and subsequent to her being prescribed 5 g / day yokukansan ( tj-54 ; tsumura co , tokyo , japan ) within a week .
yokukansan ( in japan ) is a traditional asian herbal medicine that has been approved for insomnia and anxiety disorders by the japanese ministry of health , labour and welfare ; prescriptions for it are covered under the national health insurance plan .
a 56-year - old woman who had no family history of ad showed a 5-year history of cognitive decline .
her cranial mri images showed moderate atrophy of the parietal lobes , mild enlargement of the lateral ventricle , and no ischemic changes . upon clinical examination , there was apathy , but no neurological abnormalities were found .
we found no drug - related or physical or neurological factors to have caused her cognitive disturbance . from these findings
two weeks after the extension study with a rivastigmine patch ( 18 mg / day ) , she was prescribed donepezil ( 3 mg / day ) according to the wishes of her husband .
she began to go out early in the morning 4 days after starting donepezil ; she loitered all day and became agitated and aggressive toward family members 6 days later .
her npi scores before taking donepezil and when undergoing npi were 20 and 40 points , respectively ( figure 1b ) .
her loitering , agitation , and aggression decreased after her discontinuation of donepezil and subsequent to her being prescribed tandospirone ( 30 mg/ day ) and yokukansan ( 7.5 g / day ) within a week .
it is a member of the azapirone and piperazine chemical classes and is closely related to other agents such as buspirone and gepirone .
a 76-year - old woman without family history of ad presented with a 5-year history of cognitive decline and a decrease in her activities of daily living .
she needed the help of her family for daily activities such as excretion , bathing , and changing her clothes . on the mini - mental state examination ( mmse ) ,
a cranial mri revealed moderate atrophy of the cerebral cortices , an enlargement of the inferior horn of the right lateral ventricle , and a slight ischemic change in the deep white matter .
brain bloodflow scintigraphy showed a right dominant decline in the parietotemporal lobes and a decline in the posterior cingulate gyrus .
there was no use of drugs or physical or neurological factors to explain her cognitive disturbance . based on these findings
the patient participated in the clinical study of rivastigmine  a 24-week , multicenter , randomized , double - blind , placebo - controlled , parallel - group , dose - finding study evaluating the efficacy , safety , and tolerability of the once - daily rivastigmine patch formulation in patients with probable ad ( mmse score of 1020)3 and an accompanying , open - label , 52-week , extension study .
one week after the extension study with a rivastigmine patch ( 18 mg / day ) , she started treatment with donepezil at a dose of 3 mg / day .
she suffered from insomnia 3 days later and did not follow family advice , eg , walking around outside regardless of bad weather and ending up being protected by the police . in spite of it being a very hot day , she went out and lost her way , and was subsequently put under protective custody at a police station .
consequent to these occurrences , she was admitted to national hospital organization , kikuchi hospital .
her scores on the neuropsychiatric inventory ( npi ) before taking donepezil and at admission were 17 and 38 points , respectively ( figure 1a ) .
her agitation , irritability , and loitering tendencies improved after her discontinuation of donepezil and subsequent to her being prescribed 5 g / day yokukansan ( tj-54 ; tsumura co , tokyo , japan ) within a week .
yokukansan ( in japan ) is a traditional asian herbal medicine that has been approved for insomnia and anxiety disorders by the japanese ministry of health , labour and welfare ; prescriptions for it are covered under the national health insurance plan .
a 56-year - old woman who had no family history of ad showed a 5-year history of cognitive decline .
her cranial mri images showed moderate atrophy of the parietal lobes , mild enlargement of the lateral ventricle , and no ischemic changes . upon clinical examination , there was apathy , but no neurological abnormalities were found .
we found no drug - related or physical or neurological factors to have caused her cognitive disturbance . from these findings
two weeks after the extension study with a rivastigmine patch ( 18 mg / day ) , she was prescribed donepezil ( 3 mg / day ) according to the wishes of her husband .
she began to go out early in the morning 4 days after starting donepezil ; she loitered all day and became agitated and aggressive toward family members 6 days later .
her npi scores before taking donepezil and when undergoing npi were 20 and 40 points , respectively ( figure 1b ) .
her loitering , agitation , and aggression decreased after her discontinuation of donepezil and subsequent to her being prescribed tandospirone ( 30 mg/ day ) and yokukansan ( 7.5 g / day ) within a week .
it is a member of the azapirone and piperazine chemical classes and is closely related to other agents such as buspirone and gepirone .
our patients suffered from deterioration of bpsd associated with a switching from rivastigmine to donepezil . comparing the pharmacological profiles of donepezil and rivastigmine , it is known that donepezil is a specific acetylcholinesterase inhibitor , while rivastigmine is a dual cholinesterase inhibitor ( chei ) that is capable of inhibiting butyrylcholinesterase , another enzyme involved in acetylcholine degradation.4 the different efficacies of these cheis are also reported in clinical settings;57 however , it is not evident that these differences are due to the different pharmacological profiles mentioned above .
it is also conceivable that the pharmacological differences among the cheis result in different profiles of adverse events , including neuropsychiatric symptoms . the occurrence and presentations of bpsd varied between our patients , and
the manifestation of bpsd may be affected by patient profiles , including personality and environmental factors such as caregiving . in ad patients ,
sensitivity to psychoactive drugs may also vary , and some patients can be prone to drug - induced psychiatric events.8 it is reported that some ad patients show hostility or agitation accompanying their donepezil treatment,911 suggesting the possible exacerbation of neuropsychiatric symptoms by donepezil treatment .
we occasionally experience dementia patients whose bpsd has been worsened by donepezil.12,13 it can be hypothesized that , in some patients , neuropsychiatric symptoms may be induced and enhanced by donepezil but that they are not , or are less evidently so , by rivastigmine . with this hypothesis , we should carefully evaluate the bpsd of patients after switching cheis , because the switch may cause bpsd to deteriorate , as it did in our patients .
it also should be mentioned that we should be cautious when switching the medication in the reverse direction , ie , from donepezil to rivastigmine , as the switch may potentially cause other adverse effects in some patients . besides the two drugs different pharmacological profiles
, their difference in formulation might be related to the deteriorated bpsd in the observed cases .
rivastigmine is applied as a patch formulation , while donepezil is an oral - delivery formulation . with the patch
, the pharmacologically active ingredient is continuously absorbed through the skin barrier composed of the epidermis and dermis , resulting in an unfluctuating blood concentration of the compound throughout the treatment.14 the pharmacokinetic profile of donepezil is known to be preferable , not least due to its long plasma half - life ( t1/2 ) resulting in a considerably high trough level with oral applications at 24-hour intervals . however , like other oral medications , peak plasma concentration ( cmax ) after oral administration is unavoidable . in this regard , the deterioration in behavioral and psychological symptoms observed in the two clinical cases have been caused by their different pharmacokinetic profiles .
the high peak - blood concentration of chei or the temporal fluctuation of the blood concentration may have caused such adverse symptoms .
it may also be possible that both pharmacological and pharmacokinetic differences were involved in the cases we observed .
nevertheless , the cases should be considered , in the context of pharmacology and pharmacokinetics , to have been exceptional ones that showed patients with profiles prone to negative effects from donepezil treatment .
a randomized , double - blind clinical trial comparing the efficacy and safety of rivastigmine and donepezil5 showed no significant difference in overall efficacy as determined by the severe impairment battery.15 a slight but significant difference was observed in the alzheimer s disease cooperative study - activities of daily living inventory,16 the assessment battery on activities of daily living , suggesting pharmacological difference between the two medications.5 in the study , gastrointestinally adverse events were more frequent in the patients treated with rivastigmine , because it was given in capsule instead of patch formulation .
as different responses to different medications may have occurred only in some patients , it is not possible to detect such responses in large clinical trials involving hundreds of patients . the discovery of biomarkers to discriminate patients with symptoms exacerbated by participation , together with careful and intensive observation of patients , will be needed to generalize our observations in this report .
we have reported on two ad patients who showed deterioration of bpsd induced by switching from rivastigmine to donepezil .
our observations might give general practitioners information useful for noticing possible unfavorable reactions caused by changing medications from the same therapeutic class .
further collection and verification of cases is required to find patient populations with the optimum medications and/or risk factors , in order to determine the most appropriate medications to administer , according to the symptoms , disease stages , or putative subtypes of the disease .
 rivastigmine , galantamine , and memantine , in addition to donepezil , which has been on the market over 10 years , have been available for the treatment of alzheimer s disease ( ad ) since 2011 in japan , leading a new stage in the medical treatment of ad . 
 we studied two ad patients showing sudden deterioration of behavioral and psychological symptoms of dementia ( bpsd ) associated with switching from rivastigmine to donepezil after the clinical trial of rivastigmine . in the patients , rivastigmine seemed to be more beneficial than donepezil for the control of bpsd . 
 although it was not obvious whether their different responses to the two cholinesterase inhibitors were due to the different pharmacological profiles , ie , the presence of inhibition of butyrylcholinesterase in rivastigmine , a particular cholinesterase inhibitor might be more effective in particular ad cases . 
 further investigations are needed to confirm the difference , and to identify the measures for selecting the most appropriate medication for each ad patient . 
Introduction
Cases
Patient 1
Patient 2
Discussion