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Keywords:

  • Alzheimer type-dementia;
  • cognitive function;
  • donepezil;
  • non-responder;
  • responder

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Background:  Donepezil is effective in maintaining the cognitive function of patients with mild to moderate Alzheimer's disease (AD). However, not all patients respond to donepezil. In the present study, we examined the clinical features of responders and non-responders to long-term donepezil treatment.

Methods:  The present retrospective study was performed on 95 AD outpatients who had been taking donepezil for ≥2 years. All subjects underwent periodic examinations of cognitive function, namely Mini-Mental State Examination (MMSE) and Rorschach Cognitive Index (RCI), as well as clinical evaluations using the Clinical Dementia Rating (CDR) scale. Patients were divided into three groups as follows: (i) the ‘maintained’ group (MG), in which the global CDR score was maintained over the ≥2 years of treatment; (ii) the ‘declined’ group (DeG), in which the global CDR score increased one rank over the treatment period; and (iii) the ‘obvious and rapid decline’ group (ORDeG), in which the global CDR score increased two ranks early during the treatment period. Clinical features, treatment outcome, the time lag between a caregiver's recognition of the onset of dementia and the start of treatment, behavioral and psychological symptoms of dementia (BPSD), and cognitive functions were compared between the three groups.

Results:  Patients in the ORDeG (i.e. non-responders) were significantly younger and had a longer time lag between the onset of dementia and the start of treatment than patients in the MG (< 0.05). Of note, patients in the ORDeG had a longer period of executive dysfunction before treatment started than patients in the MG (P < 0.001). Evaluation of cognitive function revealed that mean changes from baseline on the MMSE and RCI were significantly lower for patients in the ORDeG compared with the MG at 8 and 4 months, respectively (P < 0.001 and P < 0.05, respectively).

Conclusion:  Donezepil non-responders are likely to be younger and to have a longer time lag between the onset of dementia and the start of treatment, in particular a longer duration of executive dysfunction. Furthermore, the non-responders do not demonstrate maintenance of cognitive functions in the short term. Thus, the early diagnosis of dementia and prompt initiation of donepezil treatment is indicated for a good outcome. To this end, it is important to educate people to recognize a deterioration of executive function in daily living.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive course and development in middle to late life. Donepezil has been shown to be effective in maintaining cognitive function for over 2 years in patients with mild to moderate AD.1 However, not all patients respond to donepezil and the prediction of treatment efficacy prior to the initiation of treatment is difficult.1,2 In a previous study, we found that when a beneficial effect of donepezil is seen on cognitive function in the short term, it is more likely that beneficial effects of donepezil treatment can be expected over the longer term (i.e. 2 years).1 Although these findings provide support for the efficacy of donepezil treatment, the clinical features of non-responders to long-term donepezil treatment remained unknown. Thus, in the present study, we examined the clinical features of responders and non-responders to long-term donepezil treatment.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

In the present study, the diagnosis of dementia and the likely prognosis were explained to all subjects and their caregivers, as were the benefits and potential drawbacks associated with donepezil treatment. After an oral explanation of the study had been given, informed consent was obtained from all subjects and their caregivers. The present study was approved by the ethics committee of Okamoto clinic.

The present retrospective study investigated 95 AD outpatients (28 men and 67 women) who had been taking donepezil for ≥2 years. The mean (±SD) age of the patients prior to starting treatment was 76.9 ± 5.9 years (range 61–88 years). All patients had visited Okamoto Clinic between January 2000 and June 2007 and fulfilled the diagnostic criteria for probable AD on the National Institute of Neurological and Communicative Disorder and Stroke, Alzheimer's disease and Related Disorders Association (NINCDS-ADRDA).3 None of the patients had a history of cerebrovascular or neurological disease. The diagnosis of AD was supported by data from brain computed tomography (CT) and/or magnetic resonance imaging (MRI). All patients underwent periodic examination of cognitive function using the Mini-Mental State Examination (MMSE)4 and Rorschach Cognitive Index (RCI),5,6 as well as clinical evaluations based on the Clinical Dementia Rating (CDR) scale.7 Clinical and cognitive evaluations were performed prior to initiation of donepezil treatment and then at 4-monthly intervals thereafter. Independent of the diagnostic assessments, the MMSE and RCI were administered by experienced clinical psychologists. The results of these two tests can be used as an indicators of abstract thinking and/or recognition.

Before beginning donepezil treatment, nine of the 95 patients were evaluated as CDR 0.5, with the remaining 86 patients evaluated as CDR 1. The clinical efficacy of donepezil was determined on the basis of changes in the global CDR score from baseline at 24–36 months. Patients were divided into three groups as follows: (i) the ‘maintained’ group (MG), in which the global CDR score was maintained over the ≥2 years of treatment; (ii) the ‘declined’ group (DeG), in which the global CDR score increased one rank (i.e. from CDR 0.5 to 1 or from CDR 1 to2) over 36 months of treatment; and (iii) the ‘obvious and rapid decline’ group (ORDeG), in which the global CDR score increased two ranks (i.e. from CDR 0.5 to CDR 2 or from CDR 1 to CDR 3) early during the treatment period (i.e. within the first 24 months of treatment). Eleven patients, who could not be classified as either MG or DeG because the duration of their treatment was <36 months, were excluded from the analysis.

Between January 2000 and June 2007, 155 outpatients with mild to moderate AD (CDR 0.5 or 1) visited the Okamoto Clinic. However, the present study was performed on patients who had been taking donepezil for ≥2 years. Of the original 155 patients, 37 (24%) discontinued donepezil treatment after <12 months and 23 of the remaining 118 patients (19.5%) discontinued treatment after <24 months. Thus, data for 95 patients were analyzed in the present study. However, we did examine the main reasons why patients had discontinued donepezil treatment after <24 months because this group may include patients who could be classified as non-responders. The most frequent reasons for discontinuation of donepezil treatment were the appearance of the BPSD (including hostility and delusions of being stolen from; n = 19), problems with drug compliance (n = 13), admission to hospital due to physical illness (n = 8), and admission to a home for the aged (n = 6). Relatively few patients discontinued donepezil because of progression to advanced dementia (n = 3). Thus, although it is possible that some of the patients who discontinued donepezil early were non-responders, there was no clear indication that significant numbers of non-responders were in this group. On this basis, we restricted our study to AD outpatients who had been taking donepezil for ≥2 years.

In the present study, the CDR Sum of Boxes was not used; rather, the global CDR score was used because we divided patients into three groups on the basis of changes in the severity of their dementia after 24–36 months compared with baseline.

Statistical analysis

Differences in the clinical features, treatment outcome (age, sex ratio, CDR before treatment, MMSE and RCI scores before treatment, time until discontinuation of treatment, duration of maintenance of initial CDR, time when CDR increased one rank, duration of maintenance of the one-rank increase in CDR and time lag from the onset of dementia until the start of donepezil treatment), and mean changes from baseline on the MMSE and RCI were evaluated between the three groups using the χ2-test and one-way analysis of variance (anova). Tukey's method was used for multiple comparisons. Within each group, MMSE and RCI score was compared before treatment and at 4-monthly intervals thereafter using paired t-tests. Statistical analyses were conducted with spss for windows (version 14.0; SPSS, Chicago, IL, USA).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Patient demographics

All patients enrolled in the present study were treated with donepezil (5 mg/day) over a 2-year period and, during that time, underwent periodic evaluation of cognitive function and CDR. Patient demographics for each group are given in Table 1. No significant differences were found between the three groups in terms of sex ratio, CDR, MMSE and RCI before treatment. Significant differences were observed for age at the start of treatment, with patients in the ORDeG being significantly younger than those in the MG (P < 0.05). As shown in Fig. 1, there was a relatively high proportion of younger patients in the ORDeG, but a much lower proportion of older patients in this group.

Table 1.  Patient demographics and treatment outcome
 MGDeGORDeG
(n = 48)(n = 20)(n = 16)
  1. Unless indicated otherwise, data are given as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 compared with the ‘maintained’ group (MG); P < 0.05, ††P < 0.01, †††P < 0.001 compared the ‘declined’ group (DeG).

  2. ORDeG, ‘obvious and rapid decline’ group; CDR, Clinical Dementia Rating; MMSE, Mini-Mental State Examination; RCI, Rorschach Cognitive Index.

Age (years)77.7 ± 5.877.4 ± 5.873.0 ± 6.1*
 Range (years)63–8861–8663–82
Sex (M/F)13/354/167/9
CDR score before treatment1.0 ± 0.11.0 ± 0.20.9 ± 0.2
(0.5–1)(0.5–1)(0.5–1)
MMSE score before treatment21.2 ± 2.320.6 ± 2.720.1 ± 2.7
RCI score before treatment−1.2 ± 2.4−1.6 ± 1.9−1.1 ± 3.3
No. patients discontinuing treatment (n)3 (6%)3 (15%)11 (69%)
Time until discontinuation of treatment (months)31.7 ± 5.931.7 ± 3.227.1 ± 3.7
(25–36)(28–34)(24–32)
Duration of maintenance of initial CDR rank (months)35.6 ± 1.821.4 ± 7.0***9.3 ± 4.3***†††
(24–36)(8–32)(4–20)
Time when CDR increased one rank (months) 25.4 ± 7.012.5 ± 3.3†††
 (12–36)(0–16)
Duration of maintenance of one rank CDR increase (months) 14.2 ± 7.88.8 ± 3.6
 (4–28)(0–16)
image

Figure 1. Age of patients in each of the three groups: (i) the ‘maintained’ group (MG), in which the global Clinical Dementia Rating (CDR) score was maintained over the ≥2 years of treatment; (ii) the ‘declined’ group (DeG), in which the global CDR score increased one rank over the treatment period; and (iii) the ‘obvious and rapid decline’ group (ORDeG), in which the global CDR score increased two ranks early during the treatment period.

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Of the final 84 patients who were subjected to analysis, three of 48 (6%) in the MG, three of 20 (15%) in DeG, and 11 of 16 (69%) in the ORDeG discontinued treatment. In terms of the time at which treatment was discontinued, there were no significant differences between the three groups. The duration of maintenances of initial CDR was significantly shorter for patients in the ORDeG compared with those in the MG and DeG (both P < 0.001), and that in the DeG was significantly shorter than that in the MG (P < 0.001). The CDR increased one rank much earlier in the ORDeG than in the DeG (P < 0.001). After the CDR had increased one rank, the new CDR was maintained for a much shorter period of time in the ORDeG than in the DeG (P < 0.05). For patients in the ORDeG, the average time when CDR increased two ranks was 22.0 ± 3.3 months.

In summary, patients in the ORDeG were more likely to discontinue donepezil treatment, maintained initial CDR for a shorter period of time, exhibited increased CDR (one rank) earlier and, again, maintained the increased CDR for a shorter period of time than did patients in the other two groups. Thus, patients in the ORDeG were defined as non-responders, whereas patients in the other two groups were defined as responders to long-term donepezil treatment. In terms of clinical features, non-responders were significantly younger than responders at the start of donepezil treatment.

Onset of dementia

The time lag from the onset of dementia (as determined on the basis of information provided by caregivers) until the start of donepezil treatment is given in Table 2. Data are presented separately for the time lag between the start of donepezil treatment: (i) a caregiver's recognition of overt memory deficits; and (ii) a caregiver's recognition of overt deficits in executive function (unable to continue working, doing the housework, socializing etc.).

Table 2.  Time lag from the onset of dementia, as reported by caregivers, until the start of donepezil treatment
 MGDeGORDeG
  1. Data are the mean ± SD. *P < 0.05, ***P < 0.001 compared with the ‘maintained’ group (MG); †††P < 0.001 compared the ‘declined’ group (DeG).

  2. ORDeG, ‘obvious and rapid decline’ group

Time from overt memory deficit until treatment (months)13.1 ± 9.821.9 ± 15.1*28.1 ± 18.0***
Time from executive dysfunction until treatment (months)12.4 ± 14.322.5 ± 17.342.8 ± 19.5***†††

The time lag between initiation of donepezil treatment of a caregiver's recognition of overt memory deficit was significantly longer for patients in the ORDeG and DeG than in the MG (P < 0.001 and P < 0.05, respectively). Again, the time lag between the start of donepezil treatment and a caregiver's recognition of executive dysfunction was significantly longer for patients in the ORDeG compared with that for patients in the MG and DeG (both P < 0.001). On the basis of these findings, non-responders (i.e. those in the ORDeG) tend to have a longer time lag from the onset of dementia until donepezil treatment is started.

Figure 2 shows the time lag between the onset of executive dysfunction until the start of donepezil treatment and the duration of the maintenance of initial CDR. There were no significant differences between the groups for the sum of the duration of these two factors. Although there are some limitations regarding the use of information provided by caregivers, the time lag between the onset of dementia and the start of donepezil treatment may be predictor of long-term treatment outcome. In particular, the time lag between the onset of executive dysfunction and the start of donepezil treatment may be a significant predictor of long-term treatment outcome.

image

Figure 2. Time lag from the onset of executive dysfunction until the start of donepezil treatment and the duration of maintenance of the initial Clinical Dementia Rating (CDR) score in the ‘maintained’ group (MG), ‘declined’ group (DeG), and the ‘obvious and rapid decline’ group (ORDeG).

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Cognitive evaluation

The results of cognitive evaluations using the MMSE and RCI in the three groups are given in Tables 3 and 4. Patients in the ORDeG were excluded from the analysis of data at 28–36 months because a significant number of patients in this group had discontinued treatment after 24 months.

Table 3.  Changes in Mini-Mental State Examination scores at various time points during donepezil treatment
GroupMMSE score
Before treatmentDuration of donepezil treatment
4 months8 months12 months16 months20 months24 months28 months32 months36 months
  1. Data are the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 compared with before treatment within the same group.

  2. MMSE, Mini-Mental State Examination; MG, maintained group; DeG, declined group; ORDeG, obvious and rapid decline group.

MG21.2 ± 2.321.5 ± 2.322.4 ± 2.5**21.7 ± 2.622.3 ± 2.7*21.2 ± 2.921.4 ± 2.720.8 ± 2.820.6 ± 3.220.2 ± 3.0*
DeG20.6 ± 2.720.0 ± 3.219.8 ± 2.219.4 ± 2.818.2 ± 2.6***18.4 ± 2.3***17.4 ± 3.2***16.6 ± 2.6***16.2 ± 2.3***15.7 ± 2.6***
ORDeG20.1 ± 2.719.8 ± 2.717.9 ± 3.8**16.2 ± 30***14.6 ± 4.5***13.6 ± 4.6***11.6 ± 4.6***   
Table 4.  Changes in Rorschach Cognitive Index scores at various time points during donepezil treatment
GroupRCI score
Before treatmentDuration of donepezil treatment
4 months8 months12 months16 months20 months24 months28 months32 months36 months
  1. Data are the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001 compared with before treatment within the same group.

  2. RCI, Rorschach Cognitive Index; MG, maintained group; DeG, declined group; ORDeG, obvious and rapid decline group.

MG−1.2 ± 2.4−0.3 ± 2.6**−0.7 ± 2.9−0.5 ± 2.6−0.8 ± 2.8−1.0 ± 2.7−1.1 ± 2.8−1.5 ± 30−1.3 ± 30−1.3 ± 2.8
DeG−1.6 ± 1.9−1.0 ± 2.7−1.4 ± 2.7−1.4 ± 3.0−1.3 ± 2.8−1.7 ± 2.9−2.3 ± 2.5−3.1 ± 3.3*−3.6 ± 3.0**−5.1 ± 3.4***
ORDeG−1.1 ± 3.3−1.9 ± 2.9−2.0 ± 3.4−2.6 ± 3.6−3.1 ± 2.6*−4.2 ± 3.2**−4.9 ± 3.5*   

In the MG, compared with MMSE scores prior to treatment, significantly higher scores were seen after 8 months (t = 2.8; P < 0.01) and 16 months (t = 2.3; P < 0.05), but lower scores were seen after 36 months (t = 2.1; P < 0.05). Patients in the DeG had significantly lower MMSE scores after 16, 20, 24, 28, 32, and 36 months treatment with donepezil (t = 3.8, < 0.001; t = 3.7, < 0.001; t = 4.4, < 0.001; t = 6.4, < 0.001; t = 6.9, < 0.001; and t = 9.0, < 0.001, respectively). Similarly, patients in the ORDeG had significantly lower MMSE scores after 8, 12, 16, 20, and 24 months donepezil treatment (t = 3.4, < 0.01; t = 5.2, < 0.001; t = 6.3, < 0.001; t = 5.9, < 0.001; and t = 7.2, < 0.001, respectively).

Patients in the MG had significantly higher RCI scores after 4 months donepezil treatment compared with scores prior to the initiation of treatment (t = 2.9; P < 0.01). Significantly lower RCI scores were seen in patients in the DeG after 28, 32, and 36 months treatment (t = 2.4, < 0.05; t = 3.5, < 0.01; and t = 4.3, < 0.001, respectively). Similarly, patients in the ORDeG had significantly lower RCI scores after 16, 20, and 24 months treatment (t = 2.2, < 0.05; t = 3.0, < 0.01; and t = 2.7, < 0.05, respectively).

Figures 3 and 4 show means changes from baseline of MMSE and RCI scores in the three groups. Patients in the DeG and ORDeG exhibited significantly lower changes in MMSE scores (Fig. 3) than did patients in the MG (at 8 and after 16–36 months, and after 8–24 months, respectively), with the changes in the ORDeG being significantly lower than those seen in the DeG (from 12 to 24 months). Similarly, mean changes in RCI scores from baseline (Fig. 4) were significantly lower in the ORDeG than in the MG (at 4 and after 12–24 months), with a tendency for lower changes in RCI scores in the DeG compared with the MG that reached significance only at 36 months. As for changes in MMSE scores, changes in RCI scores were lower in the ORDeG than in the DeG, reaching statistical significance at 20 and 24months (Figs 3,4).

image

Figure 3. Mean changes (from baseline) on the Mini-Mental State Examination (MMSE) in the ‘maintained’ group (MG), ‘declined’ group (DeG), and the ‘obvious and rapid decline’ group (ORDeG) over the period of donepezil treatment. Data are the mean. *P < 0.05, **P < 0.01, ***P < 0.001 compared with the MG; P < 0.05, ††P < 0.01, †††P < 0.001 compared with the DeG.

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image

Figure 4. Mean changes (from baseline) on the Rorschach Cognitive Index (RCI) in the ‘maintained’ group (MG), ‘declined’ group (DeG), and the ‘obvious and rapid decline’ group (ORDeG) over the period of donepezil treatment. Data are the mean. *P < 0.05, **P < 0.01, ***P < 0.001 compared with the MG; P < 0.05, ††P < 0.01, †††P < 0.001 compared with the DeG.

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On the basis of these findings, patients in the ORDeG exhibit earlier deterioration of cognitive function than do patients in the other two groups. Thus, non-responders do not show any maintenance of cognitive function, which is known to be a short-term benefit of donepezil treatment.

Behavioral and psychological symptoms of dementia

Prior to donepezil treatment, 18 of 84 subjects (21%) had some form of BPSD and two patients were receiving psychiatric medication for the treatment of depression and anxiety (clotiazepam n = 1; paroxetine and brotizolam n = 1). These two patients were included in the MG and donepezil treatment was not influenced by the psychiatric medication.

As indicated in Table 5, 20 of 84 subjects (24%) exhibited episodic or continuous BPSD during the treatment period. Symptoms of BPSD were more frequent in the ORDeG (56%) than in the MG and DeG (15% vs 20%, respectively). The time lag from the start of treatment until the onset of BPSD in the MG, DeG and ORDeG was 17.7 ± 8.3, 25.3 ± 5.3, and 19.9 ± 2.4 months, respectively. Hyperactivity, hostility, and delirium developed with the progression of dementia in the DeG and ORDeG.

Table 5.  Behavioral and psychological symptoms of dementia that appeared during the treatment period
 MGDeGORDeG
(n = 48)(n = 20)(n = 16)
  1. Data are the number of patients in each group, with percentages in parentheses, except for the time from the start of donepezil treatment until the onset of behavioral and psychological symptoms of dementia (BPSD), which is presented as the mean ± SD.

  2. MG, maintained group; DeG, declined group; ORDeG, obvious and rapid decline group.

Episodic BPSD2 (4%)2 (10%)3 (19%)
Continuous BPSD5 (10%)2 (10%)6 (38%)
Depression and/or disinclination421
Insomnia  1
Anxiety   
Hyperactivity  4
Hostility112
Delusion1  
Delirium111
Time from the start of donepezil treatment until onset of BPSD (months)17.7 ± 8.325.3 ± 5.319.9 ± 2.4
No. patients given additional psychiatric medication5 (10%)2 (10%)5 (31%)

Additional psychiatric medication was started in five patients in the MG (paroxetine n = 3; tiapride n = 2), in two patients in the DeG (paroxetine n = 2), and in five patients in the ORDeG (flunitrazepam n = 1; tiapride n = 4). Of the 12 patients who received additional psychiatric medication, five in the ORDeG discontinued donepezil treatment because of BPSD, such as hyperactivity and hostility, but the remaining seven patients in the MG and DeG continued donepezil treatment with the additional psychiatric medication.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

In the present study, non-responders to long-term donepezil treatment were defined as patients who exhibited an increase on the CDR scale of two ranks (e.g. CDR from 0.5 to 2 or CDR from 1 to 3) within the 2-year treatment period. Sixteen patients (19%) in the ORDeG were defined as non-responders to long-term donepezil treatment because of rapid and obvious advances in dementia. Conversely, CDR scales were maintained in patients in the MG (n = 48) over the treatment period. In the DeG (n = 20), CDR scales were maintained for 21.4 ± 7.0 months, after which the CDR increased one rank and was maintained at this level for a further 14.2 ± 7.8 months treatment. Thus, these latter two groups were defined as responders to long-term donepezil treatment.

There were no significant differences in CDR, MMSE, and RCI scores before treatment between the responder and non-responder groups. In previous studies, although no significant differences were found between patients in whom donepezil was effective and those in whom it was not in terms of average age, CDR, MMSE, and RCI,1,2 those patients who did not respond to treatment were significantly younger when donepezil was started. As we pointed out in our previous study,1 a prediction of the long-term effect of donepezil treatment is difficult before treatment is started; however, a younger age at the time treatment starts may indicate a poorer long-term outcome of donepezil treatment.

In the present study, the non-responders had a longer time lag from the onset of dementia as reported by their caregivers (i.e. overt memory deficit and/or executive dysfunction) until treatment started. Although there are some limitations regarding the use of information provided by caregivers, based on these results, the time lag between the onset of dementia and the start of donepezil treatment may also be used as a predictor of the long-term outcome of treatment with donepezil. In particular, the time lag between the onset of executive dysfunction and the start of treatment may prove to be a significant predictor of long-term treatment outcome. These results suggest that although the caregivers of patients in the ORDeG noticed the appearance of executive dysfunction earlier than overt memory deficit, they did not necessarily encourage the patients to seek appropriate treatment. However, it is also possible that the earlier appearance of executive dysfunction than overt memory deficit may be characteristic of patients in whom there were obvious and rapid declines in dementia and this requires further investigation.

Because AD is preceded by changes in the physiological and biochemical functions in the brain, early detection and prompt initiation of donepezil treatment is needed. So, it is important to highlight the need for the early recognition of changes in executive function in daily living.

In previous studies, we reported that when beneficial short-term effects of donepezil were seen on cognitive function, a long-term beneficial effect could also be expected at 1 and 2 years follow-up.1,2 In the present study, patients in the non-responder group showed earlier deterioration on MMSE and RCI scores compared with the responders. Furthermore, the change in RCI scores from baseline to 4 months treatment was significantly lower in the ORDeG than in the MG. Thus, non-responders did not exhibit any maintenances of cognitive function, which is a known short-term effect of donepezil treatment.

Kumagai et al.8 reported that the mean differences in Revised Hasegawa Dementia Scale (HDS-R) scores in patients in whom donepezil was not effective were approximately −6 points after 2 years and approximately −10 points after 3 years, with the long-term outcomes for patients in whom donepezil was not effective after 6 months similar to those in patients who were not treated with donepezil at all. The results of the present study also suggest that it is possible that if the detection of dementia and induction of donepezil treatment are late, patients with mild AD will progress to a more severe stage of the disease in less than 24 months.

The results of present study suggest that the short-term effects of donepezil on cognitive function may be used to identify non-responders in the early stages of treatment. Thus, as pointed out in our previous studies,1,2 periodic clinical evaluation and examination of cognitive function is extremely important for effective treatment with donepezil.

In the present study, compared with responders, non-responders were found to: (i) be younger at the time donepezil treatment was started; (ii) have a longer time lag between the onset of dementia and the start of donepezil treatment, especially in terms of the duration of executive dysfunction; and (iii) not exhibit any maintenance of cognitive function, which is a known short-term effect of donepezil treatment. Furthermore, dementia advanced more rapidly in non-responders and the frequency of BPSD was higher in the more advances stages of the disease. The development of hyperactivity and hostility during the treatment period may be one reason why donepezil treatment is discontinued in non-responders. In the present study, all patients were treated with donepezil 5 mg/day continuously throughout the treatment period. A recent study has indicated that the progression of cognitive dysfunction may be inhibited by increasing the dose of donepezil to 10 mg/day.9 Although, donepezil 5 mg/day was effective in most subjects in the present study, increasing the dose to 10 mg/day donepezil in non-responders in the early stages of treatment should be considered.

Conclusion

Donepezil non-responders were found to be younger at the time treatment was started, to have a longer time lag between the onset of dementia (especially executive dysfunction) and the start of the treatment, and not to exhibit any maintenance of cognitive function in the short term. Thus, the early detection of dementia and early induction of donepezil treatment is indicated. Social education highlighting the importance of recognizing changes in executive function in daily living is important.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES
  • 1
    Inoue J, Hoshino R, Nojima H, Okamoto N. Investigation of the short-term and long-term effect of donepezil on cognitive function in Alzheimer's disease. Psychogeriatrics 2009; 9: 2733.
  • 2
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  • 3
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