PSYCHOGERIATRICS PSYCHOGERIATRICS2016; 2015;16: ••:202–208 ••–••
doi:10.1111/psyg.12140 doi:10.1111/psyg.12140
ORIGINAL ARTICLE
Increased dosage of donepezil for the management of behavioural and psychological symptoms of dementia in dementia with Lewy bodies Yuta MANABE,1,2,3 Teruo INO,2 Katsuo YAMANAKA2 and Kenji KOSAKA3
1
Dementia Diagnosis Center, Department of Internal Medicine, Yokohama Shintoshi Neurosurgical Hospital, 3Medical Care Court Clinic, Yokohama, and 2Department of Emergency and General Internal Medicine, Fujita Health University, School of Medicine, Toyoake, Japan Correspondence: Dr Yuta Manabe MD, PhD, Dementia Diagnosis Center Department of Internal Medicine, Yokohama Shintoshi Neurosurgical Hospital, 433 Edacho, Aoba-ku, Yokohama-shi, 225-13 Japan. Email: manabe-epikuros@mue .biglobe.ne.jp Received 22 November 2013; revision received 2 April 2015; accepted 11 May 2015.
Key words: Alzheimer’s disease, behavioral and psychological symptoms of dementia, cholinesterase inhibitors, hallucination, Lewy bodies, Neuropsychiatric Inventory.
Abstract Background: As with other types of dementia, the behavioral and psychological symptoms of dementia (BPSD) can make caregiving difficult for patients with dementia with Lewy bodies (DLB). We hypothesized that administration of donepezil at an increased dose of 10 mg/day might dosedependently improve BPSD in DLB patients with relapse, after their symptoms had been controlled initially by donepezil therapy at the standard dose. Methods: The present study was as an open-label trial. We enrolled 24 patients with DLB (diagnosed according to the Consortium on Dementia with Lewy Bodies Guideline-Revised) who experienced a relapse of BPSD despite treatment with donepezil at the standard dose (5 mg/day). The donepezil dose for these patients was increased to 10 mg/day, and we evaluated the efficacy and safety of this dose escalation strategy. Results: The Neuropsychiatric Inventory (NPI) scores for BPSD showed statistically significant improvements as a result of the increased dosage, except those for anxiety and euphoria, disinhibition, irritability/lability. Highdose donepezil therapy caused gastrointestinal symptoms in 4 patients, but there were no life-threatening adverse events, such as arrhythmias, or no exacerbation of parkinsonian symptoms. Conclusions: We found that donepezil dose-dependently improved relapsing BPSD in these patients. Therefore, increasing the dosage of donepezil is a safe and effective treatment for patients with DLB who experience a relapse of BPSD.
INTRODUCTION For the management of dementing illnesses, neurologists and psychiatrists triage symptoms and select evidence-based therapies with superior safety and efficacy. We bear this principle in mind when treating dementing illnesses. Dementia with Lewy bodies (DLB) can be distinguished from other dementias because the behavioural and psychological symptoms of dementia (BPSD), including the visual hallucinations characteristic of DLB, are among the core features of this disease.1 Therefore, the choice of medication for treating BPSD in DLB should be considered carefully. Currently, acetylcholinesterase inhibitors (AChEI) are widely used as the first-line treatment for BPSD.
202 © 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
This treatment is based on the findings that BPSD are related to metabolic impairments in the frontal and temporal lobes and that AChEI improve BPSD in patients with Alzheimer’s disease (AD) by increasing acetylcholine levels in these cortical regions.2 After performing a randomized clinical trial of rivastigmine, McKeith et al. concluded that AChEI therapy was a rational choice for treating BPSD rather than antipsychotic drugs, which are dopamine type 2 receptor antagonists.3 A number of reports have indicated the AChEI donepezil and rivastigmine are both effective in treating BPSD in DLB patients.3–6 We are interested in the dose-dependent pharmacodynamics of donepezil. We previously conducted a study in six patients with probable DLB who experienced a relapse of © 2015 The Authors1 Psychogeriatrics © 2015 Japanese Psychogeriatric Society
Donepezil improves BPSD in DLB patients
Y. Manabe et al.
BPSD. During these relapses, the patients presented with visual hallucinations, behavioural disturbances, and irritability, despite ongoing donepezil therapy at the standard dose (5 mg/day). In that study, we found that donepezil safely improved BPSD when the dosage was increased to 10 mg/day.7 However, the previous study involved a very small sample of six patients and did not include statistical analysis. Therefore, we increased the number of cases and hypothesized that an increased donepezil dosage might improve or prevent relapses of BPSD in DLB patients. In the present study, we examined whether a dose escalation of donepezil was beneficial for treating BPSD in relapsing DLB patients. We found that a higher dose of donepezil safely improved relapsing BPSD in a dose-dependent manner.
METHODS Patients were diagnosed with probable DLB according to the Consensus Criteria for the Clinical Diagnosis of Probable and Possible Dementia with Lewy Bodies.1 Patients with lesions that were consistent on single-photon emission computed tomography, myocardial metaiodobenzylguanidine scintigraphy in which the cut-off point was set at 1.68 in the delayed phase heart-to-mediastinum activity ratio, and MRI were eligible for this study. We enrolled 24 outpatients in this study from the Medical Care Court Clinic from 1 April 2008 to 31 March 2013; the patients had experienced a BPSD relapse despite ongoing treatment with donepezil at 5 mg/day. The baseline characteristics of the patients are shown in Table 1. The patients had experienced a relapse of BPSD and consulted as outpatients once a month or every other month. BPSD were evaluated at every consultation by the 10 items of the Neuropsychiatric Inventory (NPI). If one item exceeded grade 6 at (at least) two consultations, the patient was considered to have had a relapse, despite ongoing treatment with 5-mg/ day donepezil. The study period was 28 days. Assessment of BPSD was performed three times: before the donepezil dosage was increased, 14 days after the increase, and 28 days after the increase. The NPI, Mini-Mental State Examination (MMSE), and Hoehn and Yahr scale (H–Y score) were used to assess BPSD, cognitive function, and the severity of motor dysfunction. For patients with BPSD relapse, donepezil was increased to 10 mg/day and was administered alone. © 2 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
Therefore, the study was considered an open-label trial. Some drugs, including memantine, herbal medicines (yi-gan san), and atypical antipsychotics (quetiapine), were not administered beginning 1 month before the study began and throughout the observation period. However, a drug could be continued at a stable dose during the observation period if it was taken regularly for at least 1 month prior to the study. Atypical antipsychotics were prohibited, even as rescue treatment. The dose of antiparkinsonian medication (levodopa/dopa-decarboxlase inhibitor combination) was increased only if the H–Y score deteriorated by ≥1 point. Electrophysiological adverse events such as QT prolongation were monitored with a 12-lead electrocardiography. Each patient and his/her primary caregiver were questioned to detect gastrointestinal symptoms such as nausea, vomiting, diarrhoea, and anorexia. If any gastrointestinal symptom occurred, domperidone was administered as a rescue treatment at a dose of up to 30 mg/day. If gastrointestinal symptoms could not be sufficiently suppressed by this rescue treatment to continue donepezil therapy, the patient was removed from the study. Domperidone-related exacerbation of parkinsonian symptoms was also monitored carefully. If parkinsonian symptoms were exacerbated with an increase of ≥1 point on the H–Y scale after concomitant use of domperidone during the observation period, the dose of donepezil was reduced to 5 mg/day and domperidone was discontinued. StatView version 5.0 software (Abacus Concepts, New Jersey, USA) was used to perform Tukey–Kramer tests to detect statistically significant differences among the NPI, MMSE, and H–Y scores. This study was approved by the Ethical Review Board of our Yokohama Shintoshi Neurosurgical Hospital of Research Ethics Committee. We obtained informed consent from each patient or his/her responsible family member after providing a written explanation that the study would involve off-label use of donepezil.
RESULTS Three of the 24 patients (patients 6, 18, and 24) developed severe gastrointestinal symptoms, which led to their discontinuation of donepezil therapy. Therefore, the analysis was performed with the remaining 21 patients.
203 © 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
204
© 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
83
84 86
77 81
74
76
84
86 84
72 78
89
83
67 75
84
79
83
80 71
83 89
2
3 4
5 6
7
8
9
10 11
12 13
14
15
16 17
18
19
20
21 22
23 24
F F
F M
M
M
F
F M
F
F
M F
M F
M
F
M
F F
F M
F
F
Sex
DPZ, YGS
DPZ, YGS, ZP
DPZ, ZP DPZ DPZ, ZP DPZ
− − LD, RPR − AMT, ETP, LD
DPZ, YGS
DPZ, YGS, ZP DPZ, ZP
DPZ, ZP
DPZ, YGS
DPZ DPZ
DPZ, YGS, CNP DPZ, YGS
DPZ, ZP
DPZ
DPZ, QTA, TZ
ETP, LD, SLG
LD, PPX, SLG DXD, ETP, LD, SLG LD
LD
ETP, LD, SLG
LD, RPR −
ETP, LD, SLG DXD, ETP, LD, SLG
LD
LD, SLG
ETP, LD, SLG
DPZ DPZ, ZP
DPZ DPZ
− DXD, LD ETP, LD, SLG −
DPZ, QTA
DPZ, YGS, ZP
ETP, LD, SLG, ZNS
ETP, LD, SLG
Previous therapy for cognitive impairment and BPSD
CD, CF, VH CD, PS, VH
CD, CF, VH CD, CF, PS, VH
CD, CF, VH
CD, PS, VH
CD, CF, PS, VH
CD, CF, PS, VH CD, CF, PS, VH
CD, PS, VH
CD, CF, PS, VH
CD, PS, VH CD, PS, VH
CD, CF, PS CD, CF, PS, VH
CD, CF, PS, VH
CD, CF, PS
CD, CF, PS
CD, PS, VH CD, CF, VH
CD, CF, VH CD, CF, PS, VH
CD, PS, VH
CD, CF, PS, VH
Core features
CP CP
OH, CP −
CP
CP
OH, CP
OH, CP OH, CP
CP
OH, CP
OH, PR OH, CP
OH, CP OH, CP
CP
CP
OH, CP
OH, CP CP
OH, CP OH, CP
CP
OH, CP
Autonomic symptoms
4 4
5 8
3
6
5
11 9
5
7
4 2
9 3
2
4
8
5 5
6 2
7
4
Disease duration (years)
0 3
0 3
1
3
4
4 4
1.5
4
2.5 1
3 4
3
3
4
3 0
0 2
4
3
H–Y score
3.5 1.5 5 1
4 2 4 5 2 3 3
5
+ − + − + − + − + + − +
− +
+ +
4 4
5 2
3
5
+
+
5 5
+
− −
5
+
4.5 1.5
4
RBD
+ −
Administration period of donepezil 5 mg/day (years)
22 26
19 18
28
14
6
12 13
24
7
24 21
19 22
9
11
16
28 14
19 16
24
12
MMSE Delusion, hallucination, agitation/aggression, irritability/lability, aberrant motor activity Hallucination, agitation/aggression, disinhibition, irritability/lability, aberrant motor activity Hallucination, dysphoria/depression, anxiety Delusion, hallucination, aberrant motor activity Hallucination, dysphoria/depression, anxiety Delusion, hallucination, agitation/aggression, apathy, irritability/lability, aberrant motor activity Euphoria, disinhibition, aberrant motor activity Depression, hallucination, dysphoria/ depression, anxiety Delusion, hallucination, aberrant motor activity Delusion, hallucination, agitation/aggression Delusion, hallucination, agitation/aggression, dysphoria/depression, anxiety, irritability/ lability, aberrant motor activity Dysphoria/depression, anxiety, apathy Hallucination, dysphoria/depression, anxiety Delusion, hallucination, irritability/lability, aberrant motor activity Dysphoria/depression, anxiety, irritability/ lability Hallucination, aberrant motor activity Delusion, hallucination, aberrant motor activity Delusion, hallucination, agitation/aggression, anxiety, irritability/lability, aberrant motor activity Delusion, hallucination, agitation/aggression, dysphoria/depression, anxiety, apathy, irritability/lability, aberrant motor activity Delusion, hallucination, agitation/aggression, dysphoria/depression, anxiety, apathy, irritability/lability, aberrant motor activity Dysphoria/depression, anxiety, apathy Delusion, hallucination, apathy, aberrant motor activity Hallucination, agitation/aggression Hallucination, irritability/lability
Areas of deterioration according to the NPI
+ +
+ +
+
+
+ +
+
+
+ +
+ +
+
+
+
+ +
+ +
+
+
Decrease of H/M ratio
+ +
+ +
+
+
+ +
+
+
+ +
+ +
+
+
+
+ +
+ +
+
+
Decrease of occipital CBF
AMT, amantadine; BPSD, behavioural and psychological symptoms of dementia; CBF, cerebral blood flow; CD, cognitive dysfunction; CF, cognitive fluctuation; CNP, clonazepam; CP, constipation; DPZ, donepezil; DXD, droxidopa; ETP, entacapone; F, female; H/M, heart-to-mediastinum activity; H–Y score, Hoehn and Yahr scale; LD, levodopa/dopa-decarboxlase inhibitor; M, male; MMSE, Mini-Mental State Examination; NPI, Neuropsychiatric Inventory; OH, orthostatic hypotension; PD, Parkinson’s disease; PPX, pramipexole; PR, Paridrosis; PS, parkinsonism; QTA, quetiapine; RBD, rapid eye movement sleep behavior disorder; RPR, ropinirole; SLG, selegiline; TZ, trazodone; VH, visual hallucination; YGS, yi-gan san; ZNS, zonisamide; ZP, zolpidem.
85
Age (years)
1
Patient number
Previous therapy for motor symptoms with PD
Table 1 Clinical data of 24 patients
Y. Manabe et al. Donepezil improves BPSD in DLB patients
© 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
3
Y. Manabe et al.
Donepezil improves BPSD in DLB patients
Figure 1 The group with statistically significant improvement on the NPI. The NPI scores for BPSD revealed statistically significant improvements in 6 of 10 attributes. In particular, visual hallucinations were significantly improved in both week 2 (P < 0.0001) and week 4 (P < 0.0001). BPSD, behavioural and psychological symptoms of dementia; NPI, Neuropsychiatric Inventory, W, week.
NPI The NPI scores for BPSD revealed statistically significant improvement in 6 out of 10 attributes, with the exceptions being anxiety, euphoria, disinhibition, and irritability/lability (Figs 1,2). Because hallucinations were the most important core feature, the change in the hallucination score in NPI is described in detail. Visual hallucinations were significantly improved in both week 2 (P < 0.0001) and week 4 (P < 0.0001). For patient 2, the hallucination score decreased from baseline in week 2, but increased slightly in week 4. However, the week 4 hallucination score still showed improvement from the baseline. In patients 7, 14, and 21, the hallucination score remained stable. The mean NPI score for hallucination was 2.80 in week 2 and 2.85 in week 4, which indicates significant improvement from the baseline score of 8.23. Furthermore, we examined the correlation between disease duration before dose escalation of donepezil and the NPI score changes after dose escalation of donepezil, as © 4 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
well as the correlation between the MMSE score before dose escalation of donepezil and NPI score changes after dose escalation of donepezil. The correlation between the disease duration and NPI score changes was not accepted in both week 2 (P = 0.31) and week 4 (P = 0.2) as well as the correlation between the MMSE score and the value of NPI score changes in both week 2 (P = 0.60) and week 4 (P = 0.3). MMSE The mean MMSE score was 18.09 in week 2 and 19.09 in week 4, and the baseline score was 18. The MMSE scores did not show statistically significant improvement in cognitive function after the donepezil dosage increase in both week 2 (P = 0.47) and week 4 (P = 0.28). H–Y score The mean H–Y score was 2.52 in week 2 and 2.47 in week 4, and the baseline score was 2.52. The H–Y
205 © 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
Y. Manabe et al.
Donepezil improves BPSD in DLB patients
Figure 2 The group that did not have statistically significant improvement on the NPI. The NPI scores for BPSD did not reveal statistical improvement in 4 of 10 attributes. Anxiety, euphoria, disinhibition, and irritability/lability were included in this group. BPSD, behavioural and psychological symptoms of dementia; NPI, Neuropsychiatric Inventory, W, week.
scores for parkinsonian symptoms were unchanged after the donepezil dosage increase in both week 2 (P = 0.45) and week 4 (P = 0.5).
reactions was 16.66%; the incidence of treatment discontinuation was 12.5%.
DISCUSSION Electrocardiography findings Electrocardiography tracings did not reveal abnormalities in the QT (normal range: 0.35–0.44) and arrhythmia that were associated with the donepezil dosage increase. Gastrointestinal symptoms Four patients (patients 6, 18, 20, and 24) experienced gastrointestinal symptoms including nausea and anorexia on the first day the donepezil dose was increased. Because their gastrointestinal symptoms were not improved by rescue therapy with domperidone, three patients (patients 6, 18, and 24) discontinued their donepezil treatment. In the present study, the incidence of gastrointestinal adverse drug
206 © 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
We investigated the efficacy and safety of donepezil when administered at an increased dose to patients with DLB who experienced a relapse of BPSD during treatment with donepezil at the standard dose. We found that donepezil dose-dependently improved relapsing BPSD in these patients. Therefore, increasing the dosage of donepezil is a safe and effective treatment for patients with DLB who experience a relapse of BPSD. BPSD are a major problem that complicates caregiving for patients with dementia, including DLB. Visual hallucinations are a core feature of BPSD in patients with DLB. In addition, hypersensitivity to neuroleptics is caused by DLB. Accordingly, AChEI are a useful treatment option because they are both © 2015 The Authors5 Psychogeriatrics © 2015 Japanese Psychogeriatric Society
Donepezil improves BPSD in DLB patients
Y. Manabe et al.
effective and safe for treating BPSD in patients with DLB. McKeith et al. first indicated rivastigmine could be used to treat patients with DLB,3 which led to other investigations that examined the efficacy and safety of AChEI for patients with DLB. Similar to rivastigmine, donepezil is an AChEI that has been evaluated in many clinical studies for the management of DLB. Donepezil was originally developed to improve cognitive functioning and to slow the progressive deterioration in AD. So why is donepezil beneficial for the management of BPSD? Sultzer et al. reported that BPSD is related to frontotemporal metabolic dysfunction, and donepezil improves BPSD by acting on the cholinergic system in these regions.2 It has also been reported that Lewy bodies can be detected in the nucleus basalis of Meynert and medial septal nucleus, where acetylcholine is released in the brain.1 Therefore, loss of neurons in these cerebral regions is more prominent in patients with DLB than in patients with AD.8–10 This finding may explain why AChEI show more efficacy in treating cognitive dysfunction and BPSD in patients with DLB than in patients with AD. AChEI show a dose-dependent intensification of their actions, and this pharmacodynamic property may explain our present finding that donepezil improved BPSD after the daily dose was increased from 5 to 10 mg. Rojas-Fernandez reported a similar conclusion,10 which was based on the findings of Perry et al. and Darreh-Shori et al.11,12 The results of this study and the known pharmacodynamics of donepezil suggest that improvement of BPSD, including visual hallucinations, can be obtained in patients with DLB by increasing the dosage of donepezil, even when the patient has experienced a relapse of BPSD while taking donepezil at the standard dose. Parkinson’s disease with dementia (PDD) is an αsynucleinopathy like DLB.13 Dubois et al. reported that donepezil improved cognition, executive function, and global status in patients with PDD in a dose-dependent manner.8 In that paper, the group receiving 10 mg daily, but not the group receiving 5 mg daily, showed a significantly improved Clinician’s Interview-Based Impression of Change plus Caregiver Input scores compared with placebos.10 This suggests that donepezil can improve cognition, executive function, and global status in PDD. The most commonly reported adverse reactions for donepezil are gastrointestinal symptoms. In a randomized control trial involving donepezil and AD patients, © 6 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
Homma et al. found a dose-dependent increase in the occurrence of gastrointestinal symptoms. In the present study, donepezil caused gastrointestinal symptoms in four patients after the dose increase.9 For three of these patients, donepezil therapy at 10 mg/ day was discontinued. Therefore, the incidence of adverse drug reactions was 16.66% and the dropout rate was 12.5% in the present study. These rates are lower than the incidence of gastrointestinal adverse drug reactions (46.9%) and the dropout rate (12.5%) reported in the Interview Form of donepezil (the Drug Information of donepezil by Eisai Co., Ltd.). Dose escalation for donepezil did not cause deterioration of parkinsonian symptoms during the observation period. Rosenbloom et al. described a patient with DLB who experienced a dose-dependent symptomatic sinus bradyarrhythmia with donepezil doses ≥5 mg.14 They concluded that, owing to underlying autonomic dysfunction, patients with DLB might be at increased risk of bradyarrhythmia with AChEI treatment. These findings indicate that donepezil is a safe treatment for patients with DLB, as well as patients with AD. Our present study had some limitations because it was a small group, open-label trial that involved a short observation period. Because of the small number of cases, the side-effects, such as cardiovascular and neurological events, need to be reexamined in a larger number of patients. Although there are limitations to open-label trials, increasing the dosage of donepezil was useful for treating relapse of BPSD in patients with DLB. Future studies should include a larger number of the patients with DLB in a randomized clinical trial.
REFERENCES 1 McKeith IG, Dickson DW, Lowe J et al. Diagnosis and management of dementia with Lewy bodies. Third report of the DLB consortium. Neurology 2005; 65: 1863–1872. 2 Sultzer DL, Mahler ME, Mandelkern MA et al. The relationship between psychiatric symptoms and regional cortical metabolism in Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 1995; 7: 476–484. 3 McKeith I, Del Ser T, Spano P et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 2000; 356: 2031– 2036. 4 Ikeda M, Mori E, Kosaka K et al. Long-term safety and efficacy of donepezil in patients with dementia with Lewy bodies: results from a 52-week, open-label, multicenter extension study. Dement Geriatr Cogn Disord 2013; 36: 229–241. 5 Mori E, Ikeda M, Kosaka K. Donepezil for dementia with Lewy bodies: a randomized, placebo controlled trial. Ann Neurol 2012; 72: 41–52.
207 © 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
Y. Manabe et al. 6 Mori S, Mori E, Iseki E, Kosaka K. Efficacy and safety of donepezil in patients with dementia with Lewy bodies: preliminary findings from an open label study. Psychiatry Clin Neurosci 2006; 60: 190–195. 7 Manabe Y, Kosaka K. Efficacy of high-dose donepezil in the treatment of neuropsychiatric symptoms in cases of dementia with Lewy bodies. Clinical Psychiatry 2009; 51: 1165–1172 (in Japanese). 8 Dubois B, Tolosa E, Katzenschlager R et al. Donepezil in Parkinson’s disease dementia: a randomized, double blind efficacy and safety study. Mov Disord 2012; 27: 1230–1238. 9 Homma A, Imai Y, Tago H et al. Donepezil treatment of patients with severe Alzheimer’s disease in a Japanese population: results from a 24-week, double-blind, placebo-controlled, randomized trial. Dement Geriatr Cogn Disord 2008; 25: 399–407. 10 Rojas-Fernandez CH. Successful use of donepezil for the treatment of dementia with Lewy bodies. Ann Pharmacother 2001; 35: 202–205.
208 © 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
Donepezil improves BPSD in DLB patients 11 Perry EK, Haroutunian V, Davis KL et al. Neocortical cholinergic activities differentiate Lewy body dementia from classical Alzheimer’s disease. Neuroreport 1994; 5: 747–749. 12 Darreh-Shori T, Meurling L, Pettersson T et al. Changes in the activity and protein levels of CSF acetylcholinesterases in relation to cognitive function of patients with mild Alzheimer’s disease following chronic donepezil treatment. J Neural Transm 2006; 113: 1791–1801. 13 Lippa CF, Duda JE, Grossman M et al. DLB and PDD boundary issues diagnosis, treatment, molecular pathology, and biomarkers. Neurology 2007; 68: 812–819. 14 Rosenbloom MH, Finley R, Scheinman MM et al. Donepezil associated bradyarrhythmia in a patient with dementia with Lewy bodies (DLB). Alzheimer Dis Assoc Disord 2010; 24: 209– 221.
© 2015 The Authors7 Psychogeriatrics © 2015 Japanese Psychogeriatric Society
doi:10.1111/psyg.12140 doi:10.1111/psyg.12140
ORIGINAL ARTICLE
Increased dosage of donepezil for the management of behavioural and psychological symptoms of dementia in dementia with Lewy bodies Yuta MANABE,1,2,3 Teruo INO,2 Katsuo YAMANAKA2 and Kenji KOSAKA3
1
Dementia Diagnosis Center, Department of Internal Medicine, Yokohama Shintoshi Neurosurgical Hospital, 3Medical Care Court Clinic, Yokohama, and 2Department of Emergency and General Internal Medicine, Fujita Health University, School of Medicine, Toyoake, Japan Correspondence: Dr Yuta Manabe MD, PhD, Dementia Diagnosis Center Department of Internal Medicine, Yokohama Shintoshi Neurosurgical Hospital, 433 Edacho, Aoba-ku, Yokohama-shi, 225-13 Japan. Email: manabe-epikuros@mue .biglobe.ne.jp Received 22 November 2013; revision received 2 April 2015; accepted 11 May 2015.
Key words: Alzheimer’s disease, behavioral and psychological symptoms of dementia, cholinesterase inhibitors, hallucination, Lewy bodies, Neuropsychiatric Inventory.
Abstract Background: As with other types of dementia, the behavioral and psychological symptoms of dementia (BPSD) can make caregiving difficult for patients with dementia with Lewy bodies (DLB). We hypothesized that administration of donepezil at an increased dose of 10 mg/day might dosedependently improve BPSD in DLB patients with relapse, after their symptoms had been controlled initially by donepezil therapy at the standard dose. Methods: The present study was as an open-label trial. We enrolled 24 patients with DLB (diagnosed according to the Consortium on Dementia with Lewy Bodies Guideline-Revised) who experienced a relapse of BPSD despite treatment with donepezil at the standard dose (5 mg/day). The donepezil dose for these patients was increased to 10 mg/day, and we evaluated the efficacy and safety of this dose escalation strategy. Results: The Neuropsychiatric Inventory (NPI) scores for BPSD showed statistically significant improvements as a result of the increased dosage, except those for anxiety and euphoria, disinhibition, irritability/lability. Highdose donepezil therapy caused gastrointestinal symptoms in 4 patients, but there were no life-threatening adverse events, such as arrhythmias, or no exacerbation of parkinsonian symptoms. Conclusions: We found that donepezil dose-dependently improved relapsing BPSD in these patients. Therefore, increasing the dosage of donepezil is a safe and effective treatment for patients with DLB who experience a relapse of BPSD.
INTRODUCTION For the management of dementing illnesses, neurologists and psychiatrists triage symptoms and select evidence-based therapies with superior safety and efficacy. We bear this principle in mind when treating dementing illnesses. Dementia with Lewy bodies (DLB) can be distinguished from other dementias because the behavioural and psychological symptoms of dementia (BPSD), including the visual hallucinations characteristic of DLB, are among the core features of this disease.1 Therefore, the choice of medication for treating BPSD in DLB should be considered carefully. Currently, acetylcholinesterase inhibitors (AChEI) are widely used as the first-line treatment for BPSD.
202 © 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
This treatment is based on the findings that BPSD are related to metabolic impairments in the frontal and temporal lobes and that AChEI improve BPSD in patients with Alzheimer’s disease (AD) by increasing acetylcholine levels in these cortical regions.2 After performing a randomized clinical trial of rivastigmine, McKeith et al. concluded that AChEI therapy was a rational choice for treating BPSD rather than antipsychotic drugs, which are dopamine type 2 receptor antagonists.3 A number of reports have indicated the AChEI donepezil and rivastigmine are both effective in treating BPSD in DLB patients.3–6 We are interested in the dose-dependent pharmacodynamics of donepezil. We previously conducted a study in six patients with probable DLB who experienced a relapse of © 2015 The Authors1 Psychogeriatrics © 2015 Japanese Psychogeriatric Society
Donepezil improves BPSD in DLB patients
Y. Manabe et al.
BPSD. During these relapses, the patients presented with visual hallucinations, behavioural disturbances, and irritability, despite ongoing donepezil therapy at the standard dose (5 mg/day). In that study, we found that donepezil safely improved BPSD when the dosage was increased to 10 mg/day.7 However, the previous study involved a very small sample of six patients and did not include statistical analysis. Therefore, we increased the number of cases and hypothesized that an increased donepezil dosage might improve or prevent relapses of BPSD in DLB patients. In the present study, we examined whether a dose escalation of donepezil was beneficial for treating BPSD in relapsing DLB patients. We found that a higher dose of donepezil safely improved relapsing BPSD in a dose-dependent manner.
METHODS Patients were diagnosed with probable DLB according to the Consensus Criteria for the Clinical Diagnosis of Probable and Possible Dementia with Lewy Bodies.1 Patients with lesions that were consistent on single-photon emission computed tomography, myocardial metaiodobenzylguanidine scintigraphy in which the cut-off point was set at 1.68 in the delayed phase heart-to-mediastinum activity ratio, and MRI were eligible for this study. We enrolled 24 outpatients in this study from the Medical Care Court Clinic from 1 April 2008 to 31 March 2013; the patients had experienced a BPSD relapse despite ongoing treatment with donepezil at 5 mg/day. The baseline characteristics of the patients are shown in Table 1. The patients had experienced a relapse of BPSD and consulted as outpatients once a month or every other month. BPSD were evaluated at every consultation by the 10 items of the Neuropsychiatric Inventory (NPI). If one item exceeded grade 6 at (at least) two consultations, the patient was considered to have had a relapse, despite ongoing treatment with 5-mg/ day donepezil. The study period was 28 days. Assessment of BPSD was performed three times: before the donepezil dosage was increased, 14 days after the increase, and 28 days after the increase. The NPI, Mini-Mental State Examination (MMSE), and Hoehn and Yahr scale (H–Y score) were used to assess BPSD, cognitive function, and the severity of motor dysfunction. For patients with BPSD relapse, donepezil was increased to 10 mg/day and was administered alone. © 2 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
Therefore, the study was considered an open-label trial. Some drugs, including memantine, herbal medicines (yi-gan san), and atypical antipsychotics (quetiapine), were not administered beginning 1 month before the study began and throughout the observation period. However, a drug could be continued at a stable dose during the observation period if it was taken regularly for at least 1 month prior to the study. Atypical antipsychotics were prohibited, even as rescue treatment. The dose of antiparkinsonian medication (levodopa/dopa-decarboxlase inhibitor combination) was increased only if the H–Y score deteriorated by ≥1 point. Electrophysiological adverse events such as QT prolongation were monitored with a 12-lead electrocardiography. Each patient and his/her primary caregiver were questioned to detect gastrointestinal symptoms such as nausea, vomiting, diarrhoea, and anorexia. If any gastrointestinal symptom occurred, domperidone was administered as a rescue treatment at a dose of up to 30 mg/day. If gastrointestinal symptoms could not be sufficiently suppressed by this rescue treatment to continue donepezil therapy, the patient was removed from the study. Domperidone-related exacerbation of parkinsonian symptoms was also monitored carefully. If parkinsonian symptoms were exacerbated with an increase of ≥1 point on the H–Y scale after concomitant use of domperidone during the observation period, the dose of donepezil was reduced to 5 mg/day and domperidone was discontinued. StatView version 5.0 software (Abacus Concepts, New Jersey, USA) was used to perform Tukey–Kramer tests to detect statistically significant differences among the NPI, MMSE, and H–Y scores. This study was approved by the Ethical Review Board of our Yokohama Shintoshi Neurosurgical Hospital of Research Ethics Committee. We obtained informed consent from each patient or his/her responsible family member after providing a written explanation that the study would involve off-label use of donepezil.
RESULTS Three of the 24 patients (patients 6, 18, and 24) developed severe gastrointestinal symptoms, which led to their discontinuation of donepezil therapy. Therefore, the analysis was performed with the remaining 21 patients.
203 © 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
204
© 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
83
84 86
77 81
74
76
84
86 84
72 78
89
83
67 75
84
79
83
80 71
83 89
2
3 4
5 6
7
8
9
10 11
12 13
14
15
16 17
18
19
20
21 22
23 24
F F
F M
M
M
F
F M
F
F
M F
M F
M
F
M
F F
F M
F
F
Sex
DPZ, YGS
DPZ, YGS, ZP
DPZ, ZP DPZ DPZ, ZP DPZ
− − LD, RPR − AMT, ETP, LD
DPZ, YGS
DPZ, YGS, ZP DPZ, ZP
DPZ, ZP
DPZ, YGS
DPZ DPZ
DPZ, YGS, CNP DPZ, YGS
DPZ, ZP
DPZ
DPZ, QTA, TZ
ETP, LD, SLG
LD, PPX, SLG DXD, ETP, LD, SLG LD
LD
ETP, LD, SLG
LD, RPR −
ETP, LD, SLG DXD, ETP, LD, SLG
LD
LD, SLG
ETP, LD, SLG
DPZ DPZ, ZP
DPZ DPZ
− DXD, LD ETP, LD, SLG −
DPZ, QTA
DPZ, YGS, ZP
ETP, LD, SLG, ZNS
ETP, LD, SLG
Previous therapy for cognitive impairment and BPSD
CD, CF, VH CD, PS, VH
CD, CF, VH CD, CF, PS, VH
CD, CF, VH
CD, PS, VH
CD, CF, PS, VH
CD, CF, PS, VH CD, CF, PS, VH
CD, PS, VH
CD, CF, PS, VH
CD, PS, VH CD, PS, VH
CD, CF, PS CD, CF, PS, VH
CD, CF, PS, VH
CD, CF, PS
CD, CF, PS
CD, PS, VH CD, CF, VH
CD, CF, VH CD, CF, PS, VH
CD, PS, VH
CD, CF, PS, VH
Core features
CP CP
OH, CP −
CP
CP
OH, CP
OH, CP OH, CP
CP
OH, CP
OH, PR OH, CP
OH, CP OH, CP
CP
CP
OH, CP
OH, CP CP
OH, CP OH, CP
CP
OH, CP
Autonomic symptoms
4 4
5 8
3
6
5
11 9
5
7
4 2
9 3
2
4
8
5 5
6 2
7
4
Disease duration (years)
0 3
0 3
1
3
4
4 4
1.5
4
2.5 1
3 4
3
3
4
3 0
0 2
4
3
H–Y score
3.5 1.5 5 1
4 2 4 5 2 3 3
5
+ − + − + − + − + + − +
− +
+ +
4 4
5 2
3
5
+
+
5 5
+
− −
5
+
4.5 1.5
4
RBD
+ −
Administration period of donepezil 5 mg/day (years)
22 26
19 18
28
14
6
12 13
24
7
24 21
19 22
9
11
16
28 14
19 16
24
12
MMSE Delusion, hallucination, agitation/aggression, irritability/lability, aberrant motor activity Hallucination, agitation/aggression, disinhibition, irritability/lability, aberrant motor activity Hallucination, dysphoria/depression, anxiety Delusion, hallucination, aberrant motor activity Hallucination, dysphoria/depression, anxiety Delusion, hallucination, agitation/aggression, apathy, irritability/lability, aberrant motor activity Euphoria, disinhibition, aberrant motor activity Depression, hallucination, dysphoria/ depression, anxiety Delusion, hallucination, aberrant motor activity Delusion, hallucination, agitation/aggression Delusion, hallucination, agitation/aggression, dysphoria/depression, anxiety, irritability/ lability, aberrant motor activity Dysphoria/depression, anxiety, apathy Hallucination, dysphoria/depression, anxiety Delusion, hallucination, irritability/lability, aberrant motor activity Dysphoria/depression, anxiety, irritability/ lability Hallucination, aberrant motor activity Delusion, hallucination, aberrant motor activity Delusion, hallucination, agitation/aggression, anxiety, irritability/lability, aberrant motor activity Delusion, hallucination, agitation/aggression, dysphoria/depression, anxiety, apathy, irritability/lability, aberrant motor activity Delusion, hallucination, agitation/aggression, dysphoria/depression, anxiety, apathy, irritability/lability, aberrant motor activity Dysphoria/depression, anxiety, apathy Delusion, hallucination, apathy, aberrant motor activity Hallucination, agitation/aggression Hallucination, irritability/lability
Areas of deterioration according to the NPI
+ +
+ +
+
+
+ +
+
+
+ +
+ +
+
+
+
+ +
+ +
+
+
Decrease of H/M ratio
+ +
+ +
+
+
+ +
+
+
+ +
+ +
+
+
+
+ +
+ +
+
+
Decrease of occipital CBF
AMT, amantadine; BPSD, behavioural and psychological symptoms of dementia; CBF, cerebral blood flow; CD, cognitive dysfunction; CF, cognitive fluctuation; CNP, clonazepam; CP, constipation; DPZ, donepezil; DXD, droxidopa; ETP, entacapone; F, female; H/M, heart-to-mediastinum activity; H–Y score, Hoehn and Yahr scale; LD, levodopa/dopa-decarboxlase inhibitor; M, male; MMSE, Mini-Mental State Examination; NPI, Neuropsychiatric Inventory; OH, orthostatic hypotension; PD, Parkinson’s disease; PPX, pramipexole; PR, Paridrosis; PS, parkinsonism; QTA, quetiapine; RBD, rapid eye movement sleep behavior disorder; RPR, ropinirole; SLG, selegiline; TZ, trazodone; VH, visual hallucination; YGS, yi-gan san; ZNS, zonisamide; ZP, zolpidem.
85
Age (years)
1
Patient number
Previous therapy for motor symptoms with PD
Table 1 Clinical data of 24 patients
Y. Manabe et al. Donepezil improves BPSD in DLB patients
© 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
3
Y. Manabe et al.
Donepezil improves BPSD in DLB patients
Figure 1 The group with statistically significant improvement on the NPI. The NPI scores for BPSD revealed statistically significant improvements in 6 of 10 attributes. In particular, visual hallucinations were significantly improved in both week 2 (P < 0.0001) and week 4 (P < 0.0001). BPSD, behavioural and psychological symptoms of dementia; NPI, Neuropsychiatric Inventory, W, week.
NPI The NPI scores for BPSD revealed statistically significant improvement in 6 out of 10 attributes, with the exceptions being anxiety, euphoria, disinhibition, and irritability/lability (Figs 1,2). Because hallucinations were the most important core feature, the change in the hallucination score in NPI is described in detail. Visual hallucinations were significantly improved in both week 2 (P < 0.0001) and week 4 (P < 0.0001). For patient 2, the hallucination score decreased from baseline in week 2, but increased slightly in week 4. However, the week 4 hallucination score still showed improvement from the baseline. In patients 7, 14, and 21, the hallucination score remained stable. The mean NPI score for hallucination was 2.80 in week 2 and 2.85 in week 4, which indicates significant improvement from the baseline score of 8.23. Furthermore, we examined the correlation between disease duration before dose escalation of donepezil and the NPI score changes after dose escalation of donepezil, as © 4 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
well as the correlation between the MMSE score before dose escalation of donepezil and NPI score changes after dose escalation of donepezil. The correlation between the disease duration and NPI score changes was not accepted in both week 2 (P = 0.31) and week 4 (P = 0.2) as well as the correlation between the MMSE score and the value of NPI score changes in both week 2 (P = 0.60) and week 4 (P = 0.3). MMSE The mean MMSE score was 18.09 in week 2 and 19.09 in week 4, and the baseline score was 18. The MMSE scores did not show statistically significant improvement in cognitive function after the donepezil dosage increase in both week 2 (P = 0.47) and week 4 (P = 0.28). H–Y score The mean H–Y score was 2.52 in week 2 and 2.47 in week 4, and the baseline score was 2.52. The H–Y
205 © 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
Y. Manabe et al.
Donepezil improves BPSD in DLB patients
Figure 2 The group that did not have statistically significant improvement on the NPI. The NPI scores for BPSD did not reveal statistical improvement in 4 of 10 attributes. Anxiety, euphoria, disinhibition, and irritability/lability were included in this group. BPSD, behavioural and psychological symptoms of dementia; NPI, Neuropsychiatric Inventory, W, week.
scores for parkinsonian symptoms were unchanged after the donepezil dosage increase in both week 2 (P = 0.45) and week 4 (P = 0.5).
reactions was 16.66%; the incidence of treatment discontinuation was 12.5%.
DISCUSSION Electrocardiography findings Electrocardiography tracings did not reveal abnormalities in the QT (normal range: 0.35–0.44) and arrhythmia that were associated with the donepezil dosage increase. Gastrointestinal symptoms Four patients (patients 6, 18, 20, and 24) experienced gastrointestinal symptoms including nausea and anorexia on the first day the donepezil dose was increased. Because their gastrointestinal symptoms were not improved by rescue therapy with domperidone, three patients (patients 6, 18, and 24) discontinued their donepezil treatment. In the present study, the incidence of gastrointestinal adverse drug
206 © 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
We investigated the efficacy and safety of donepezil when administered at an increased dose to patients with DLB who experienced a relapse of BPSD during treatment with donepezil at the standard dose. We found that donepezil dose-dependently improved relapsing BPSD in these patients. Therefore, increasing the dosage of donepezil is a safe and effective treatment for patients with DLB who experience a relapse of BPSD. BPSD are a major problem that complicates caregiving for patients with dementia, including DLB. Visual hallucinations are a core feature of BPSD in patients with DLB. In addition, hypersensitivity to neuroleptics is caused by DLB. Accordingly, AChEI are a useful treatment option because they are both © 2015 The Authors5 Psychogeriatrics © 2015 Japanese Psychogeriatric Society
Donepezil improves BPSD in DLB patients
Y. Manabe et al.
effective and safe for treating BPSD in patients with DLB. McKeith et al. first indicated rivastigmine could be used to treat patients with DLB,3 which led to other investigations that examined the efficacy and safety of AChEI for patients with DLB. Similar to rivastigmine, donepezil is an AChEI that has been evaluated in many clinical studies for the management of DLB. Donepezil was originally developed to improve cognitive functioning and to slow the progressive deterioration in AD. So why is donepezil beneficial for the management of BPSD? Sultzer et al. reported that BPSD is related to frontotemporal metabolic dysfunction, and donepezil improves BPSD by acting on the cholinergic system in these regions.2 It has also been reported that Lewy bodies can be detected in the nucleus basalis of Meynert and medial septal nucleus, where acetylcholine is released in the brain.1 Therefore, loss of neurons in these cerebral regions is more prominent in patients with DLB than in patients with AD.8–10 This finding may explain why AChEI show more efficacy in treating cognitive dysfunction and BPSD in patients with DLB than in patients with AD. AChEI show a dose-dependent intensification of their actions, and this pharmacodynamic property may explain our present finding that donepezil improved BPSD after the daily dose was increased from 5 to 10 mg. Rojas-Fernandez reported a similar conclusion,10 which was based on the findings of Perry et al. and Darreh-Shori et al.11,12 The results of this study and the known pharmacodynamics of donepezil suggest that improvement of BPSD, including visual hallucinations, can be obtained in patients with DLB by increasing the dosage of donepezil, even when the patient has experienced a relapse of BPSD while taking donepezil at the standard dose. Parkinson’s disease with dementia (PDD) is an αsynucleinopathy like DLB.13 Dubois et al. reported that donepezil improved cognition, executive function, and global status in patients with PDD in a dose-dependent manner.8 In that paper, the group receiving 10 mg daily, but not the group receiving 5 mg daily, showed a significantly improved Clinician’s Interview-Based Impression of Change plus Caregiver Input scores compared with placebos.10 This suggests that donepezil can improve cognition, executive function, and global status in PDD. The most commonly reported adverse reactions for donepezil are gastrointestinal symptoms. In a randomized control trial involving donepezil and AD patients, © 6 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
Homma et al. found a dose-dependent increase in the occurrence of gastrointestinal symptoms. In the present study, donepezil caused gastrointestinal symptoms in four patients after the dose increase.9 For three of these patients, donepezil therapy at 10 mg/ day was discontinued. Therefore, the incidence of adverse drug reactions was 16.66% and the dropout rate was 12.5% in the present study. These rates are lower than the incidence of gastrointestinal adverse drug reactions (46.9%) and the dropout rate (12.5%) reported in the Interview Form of donepezil (the Drug Information of donepezil by Eisai Co., Ltd.). Dose escalation for donepezil did not cause deterioration of parkinsonian symptoms during the observation period. Rosenbloom et al. described a patient with DLB who experienced a dose-dependent symptomatic sinus bradyarrhythmia with donepezil doses ≥5 mg.14 They concluded that, owing to underlying autonomic dysfunction, patients with DLB might be at increased risk of bradyarrhythmia with AChEI treatment. These findings indicate that donepezil is a safe treatment for patients with DLB, as well as patients with AD. Our present study had some limitations because it was a small group, open-label trial that involved a short observation period. Because of the small number of cases, the side-effects, such as cardiovascular and neurological events, need to be reexamined in a larger number of patients. Although there are limitations to open-label trials, increasing the dosage of donepezil was useful for treating relapse of BPSD in patients with DLB. Future studies should include a larger number of the patients with DLB in a randomized clinical trial.
REFERENCES 1 McKeith IG, Dickson DW, Lowe J et al. Diagnosis and management of dementia with Lewy bodies. Third report of the DLB consortium. Neurology 2005; 65: 1863–1872. 2 Sultzer DL, Mahler ME, Mandelkern MA et al. The relationship between psychiatric symptoms and regional cortical metabolism in Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 1995; 7: 476–484. 3 McKeith I, Del Ser T, Spano P et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 2000; 356: 2031– 2036. 4 Ikeda M, Mori E, Kosaka K et al. Long-term safety and efficacy of donepezil in patients with dementia with Lewy bodies: results from a 52-week, open-label, multicenter extension study. Dement Geriatr Cogn Disord 2013; 36: 229–241. 5 Mori E, Ikeda M, Kosaka K. Donepezil for dementia with Lewy bodies: a randomized, placebo controlled trial. Ann Neurol 2012; 72: 41–52.
207 © 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
Y. Manabe et al. 6 Mori S, Mori E, Iseki E, Kosaka K. Efficacy and safety of donepezil in patients with dementia with Lewy bodies: preliminary findings from an open label study. Psychiatry Clin Neurosci 2006; 60: 190–195. 7 Manabe Y, Kosaka K. Efficacy of high-dose donepezil in the treatment of neuropsychiatric symptoms in cases of dementia with Lewy bodies. Clinical Psychiatry 2009; 51: 1165–1172 (in Japanese). 8 Dubois B, Tolosa E, Katzenschlager R et al. Donepezil in Parkinson’s disease dementia: a randomized, double blind efficacy and safety study. Mov Disord 2012; 27: 1230–1238. 9 Homma A, Imai Y, Tago H et al. Donepezil treatment of patients with severe Alzheimer’s disease in a Japanese population: results from a 24-week, double-blind, placebo-controlled, randomized trial. Dement Geriatr Cogn Disord 2008; 25: 399–407. 10 Rojas-Fernandez CH. Successful use of donepezil for the treatment of dementia with Lewy bodies. Ann Pharmacother 2001; 35: 202–205.
208 © 2015 The Authors Psychogeriatrics © 2015 Japanese Psychogeriatric Society
Donepezil improves BPSD in DLB patients 11 Perry EK, Haroutunian V, Davis KL et al. Neocortical cholinergic activities differentiate Lewy body dementia from classical Alzheimer’s disease. Neuroreport 1994; 5: 747–749. 12 Darreh-Shori T, Meurling L, Pettersson T et al. Changes in the activity and protein levels of CSF acetylcholinesterases in relation to cognitive function of patients with mild Alzheimer’s disease following chronic donepezil treatment. J Neural Transm 2006; 113: 1791–1801. 13 Lippa CF, Duda JE, Grossman M et al. DLB and PDD boundary issues diagnosis, treatment, molecular pathology, and biomarkers. Neurology 2007; 68: 812–819. 14 Rosenbloom MH, Finley R, Scheinman MM et al. Donepezil associated bradyarrhythmia in a patient with dementia with Lewy bodies (DLB). Alzheimer Dis Assoc Disord 2010; 24: 209– 221.
© 2015 The Authors7 Psychogeriatrics © 2015 Japanese Psychogeriatric Society
