Post-marketing survey of donepezil hydrochloride in Japanese patients with Alzheimer's disease with behavioral and psychological symptoms of dementia (BPSD)
Associate Professor Toshihisa Tanaka MD, PhD, Department of Psychiatry, Osaka University Graduate School of Medicine, D3, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. Email: email@example.com
Background: To investigate the efficacy and safety of donepezil hydrochloride (Aricept®; Eisai Co., Ltd, Tokyo, Japan), we conducted a post-marketing survey in Japanese patients with Alzheimer's disease (AD) who also had behavioral and psychological symptoms of dementia (BPSD), such as hallucinations/delusions, wandering, and aggression, which cause the greatest burden on caregivers.
Methods: A prospective, centrally registered investigation was conducted through regular clinical settings with patients diagnosed as mild to moderate AD presenting with hallucinations/delusions, wandering, and/or aggression. The treatment period was 12 weeks and no restrictions were placed on concomitant medications.
Results: The BPSD improvement rates at last-observation-carried-forward (LOCF) were 60.1% for hallucinations/delusions, 59.6% for wandering, and 65.6% for aggression. For all symptoms, improvement rates increased with the duration of the treatment period. The BPSD deterioration rates at LOCF were 1.3% for hallucinations/delusions, 3.4% for wandering, and 1.6% for aggression. Assessment of cognitive function with both the revised Hasegawa Dementia Scale (HDS-R) and Mini-Mental State Examination (MMSE) indicated significant improvements after treatment. There were significant differences in the changes in HDS-R scores between patients whose hallucinations/delusions or wandering were improved and patients whose symptoms were not improved. Moreover, the data suggested a possible correlation between changes in hallucinations/delusions and HDS-R scores, changes in hallucinations/delusions and MMSE scores, and changes in wandering and MMSE scores. Patients in whom BPSD improved also demonstrated a greater improvement in cognitive function compared with patients in whom no improvement in BPSD was noted. Nursing burden on caregivers at LOCF showed 3.6% for ‘No burden’, 54.1% for ‘Burden decreased’, and 4.5% for ‘Burden increased.’ There was an increase in the combined ratio of ‘No burden’ and ‘Burden decreased’ in proportion with prolonged treatment period. Patients with improved BPSD had a significantly greater ratio (88.5–94.4%) of ‘No burden’ plus ‘Burden decreased’ than those patients in whom no improvement in BPSD was noted.
Conclusions: These results suggest that donepezil not only improves the cognitive dysfunction of AD patients, but may also relieve BPSD in these patients. Treatment with donepezil was also found to alleviate the burden of caregivers for approximately 60% of patients. Moreover, the results indicate that donepezil is unlikely to trigger potential risks of excessive deterioration of BPSD, which would result in a heavier burden of nursing care.
In Alzheimer's disease (AD), a variety of non-cognitive symptoms (hallucinations, delusions, sleep disturbance, aggression, wandering, and restlessness) are commonly observed in addition to the major cognitive dysfunction of AD. As those symptoms occur more frequently, the caregivers' burden increases. In recent years, these symptoms have been termed ‘behavioral and psychological symptoms of dementia’ (BPSD) and there is a worldwide search for an effective treatment for the condition.1 Although BPSD is a clinically significant syndrome in AD, comprehensive epidemiological studies have not yet been conducted and the disease mechanisms remain imperfectly elucidated.
In January 1989, clinical trials of donepezil hydrochloride (Aricept®; Eisai Co., Ltd, Tokyo, Japan; hereafter referred to as donepezil), an acetylcholinesterase inhibitor, were initiated in Japan for the treatment of AD. On 8 October 1999, donepezil was approved as a new anti-AD drug for the treatment of patients with mild to moderate AD.
Clinical trials of donepezil in Japan were conducted mainly to investigate the effects of the drug on cognitive impairment; however, the effects of donepezil on BPSD were not examined in detail. Many patients with accessory symptoms, including BPSD, are often administered psychotropic and/or hypnotic medications and these drugs may have an affect on a patient's cognition. Thus, these patients were excluded from the clinical trials performed prior to approval of the drug. In the present survey, we selected hallucinations/delusions, wandering, and aggression as the most common manifestations of BPSD that placed the heaviest burden of nursing on caregivers. We conducted a post-marketing investigation in this specific population of AD patients to confirm the efficacy and safety of donepezil, as well as its effects on BPSD, to obtain further information regarding the proper use of donepezil.
Patients diagnosed as mild to moderate AD (the indication for donepezil) showing at least one (or more) BPSD of hallucinations/delusions, wandering, and aggression were investigated. Patients with a history of donepezil administration or known hypersensitivity to donepezil or piperidine derivatives were excluded from the study.
Method of survey
A prospective, centrally registered investigation was conducted at 89 medical institutions from 1 April 2001 through to 30 September 2002. The investigating clinicians filled out the registration forms to enroll eligible patients prior to the commencement of donepezil. As listed in the dosage and administration information, 3 mg donepezil was administered orally once daily and then 5 mg was administered at Weeks 1 or 2 after the initial dose. The treatment period was 12 weeks in principle. Because our post-marketing investigation was conducted as part of routine clinical practice, the concomitant use of other drug(s) was not restricted. In all, 322 patients were registered at 69 institutions and 319 survey forms were collected from 67 institutions (48 Departments of Psychiatry, 17 Departments of Neurology, and two Departments of Neurosurgery). Table 1 lists the institutions and investigators involved in the present study.
Table 1. Institutions and investigators involved in this special investigation
|Sapporo City General Hospital||Motoji Yasuda|
|Tenshi Hospital||Ryoji Matsubara|
|Sapporo Medical University||Norihito Nakano|
|Oe Hospital||Toru Oe, Hiroki Kamada|
|Tamakoshi Hospital||Takuma Tamakoshi|
|Kensei Hospital||Kouichi Makiguchi|
|Imamura Hospital||Ken-ichi Ito|
|Yamagata University School of Medicine||Shinobu Kawakatsu|
|Sendai City Hospital||Hirotake Asano|
|Tohoku University Graduate School of Medicine||Kenichi Meguro|
|Madarame Clinic||Hitoshi Madarame|
|Sendai Higashi Neurosurgical Hospital||Mikio Suzuki|
|Sakuragaoka Medical Office||Takeyasu Fukushima|
|Hagino Clinic||Ryutaro Shimada|
|Sendai Neurological Clinic||Naoshi Okita|
|Niigata Neurosurgical Hospital||Takahiro Nakayama|
|Honda Hospital||Gen Inazuki|
|Karasuyamadai Hospital||Yasumasa Asanobu|
|Uchida Hospital||Yoshihei Denda|
|Jikoukai Hospital||Katsuhiro Nagashima|
|Hotaka Hospital||Tsuneo Yamaguchi|
|Yoshino Clinic||Akio Yoshino|
|Tokyo Metropolitan Matsuzawa Hospital||Midori Anno, Satoru Ota|
|Tokyo Musashino Hospital||Tsuyoshi Tatsuno|
|Narimasu Kosei Hospital||Makoto Tamura|
|Kawakita General Hospital||Takeshi Ochi|
|Yokufukai Geriatric Hospital||Hiroshi Isono, Nobuo Furuta, Atsushi Hamuro|
|Higashinakano Clinic||Kiichiro Iikuni|
|Nippon Medical School Tama-Nagayama Hospital||Takao Ito|
|Kashiwa Hospital, The Jikei University School of Medicine||Hiroo Kasahara, Toshihiko Hashizume, Takako Manabe, Michiaki Morita|
|Kanagawa Hospital||Makoto Sakamoto|
|Yokohama Minamikyousai Hospital||Hiroshi Kubota|
|Yokosuka Kyousai Hospital||Yoshiya Kawamura, Chang-ho Lee|
|Yokohama Stroke and Brain Center||Masahiro Yamamoto|
|Nagoya University Graduate School of Medicine||Norio Ozaki|
|Fujita Health University School of Medicine||Nakao Iwata, Tomohiro Narita, Yoshio Yamanouchi, Kazunori Kusunoki|
|Sizuoka Saiseikai General Hospital||Jin Yoshii|
|Fujieda Municipal General Hospital||Ikuo Ichikawa|
|Haguri Hospital||Yoh Awau|
|Okute Mental Hospital||Ken Eguchi|
|Suda Hospital||Hideaki Kato|
|Matsusaka Chuo General Hospital||Akira Taniguchi|
|Saiseikai Matsusaka General Hospital||Toshiyuki Sakai|
|Kansai Medical University||Toshihiko Kinoshita, Kenji Nobuhara, Masafumi Yoshimura, Tsunetaka Yoshida|
|Osaka University Graduate School of Medicine||Toshihisa Tanaka, Hiroaki Kazui, Takeshi Morihara, Golam Sadik, Takashi Kudo,|
|Osaka Police Hospital||Hitoshi Azuma, Kyoko Kyotani|
|Okubo Clinic||Keisaku Okubo|
|Ozone Hospital||Yoshiyuki Nishimoto, Masaaki Inaba, Akira Hokyo|
|Osaka City Kosaiin Hospital||Aki Nakanishi|
|Tanaka Mental Clinic||Chitaru Tanaka|
|Kinki University School of Medhicine||Akira Okada|
|Ishikawa Prefectural Takamatsu Hospital||Tatsuru Kitamura, Shinnichi Tochimoto|
|Nakagawa Hospital||Kazuhiko Katsukawa|
|Fukui Matsubara Hospital||Rokuro Matsubara, Satoru Sudo|
|Turuga Onsen Hospital||Akira Tamai|
|Kurashiki Heisei Hospital||Takeo Takao, Yoshiki Takao|
|Kinoko Espoir Hospital||Yoshikatsu Fujisawa|
|Hiroshima Prefectural Hospital||Yoko Otagaki, Yasuyuki Iwamoto, Harufumi Yonezawa|
|National Sanatorium Kamo Hospital||Tokumi Fujikawa, Yukio Sato|
|University of Occupational and Environmental Health||Jun Nakamura, Shuji Soeda|
|Kokura Gamoh Hospital||Yoshishige Ida|
|Torigoe Neurosurgical Clinic||Ryuichiro Torigoe|
|Hizen Psychiatric Center||Takefumi Yuzuriha|
|Hizen National Hospital||Hiroshi Koga|
|Miyazaki Medical College||Yoshio Mitsuyama, Yuta Ishizuka|
|Kagoshima University Faculty of Medicine||Morikuni Takigawa, Tetsuya Tsudome|
Changes in BPSD
Clinicians evaluated hallucinations/delusions, wandering, and aggression, prior to donepezil administration and then again at Weeks 4, 8 and 12 (or cessation) after the administration of the first dose of donepezil. Changes from baseline were determined by grading the symptoms on a three-point scale as follows: 1, improved; 2, unchanged; 3, worsened. Any nonevaluable symptoms were noted as such. When other treatments were given for BPSD, the drugs used (name, class etc.) were recorded.
Cognitive function was evaluated using the revised Hasegawa Dementia Scale (HDS-R) or the Mini-Mental State Examination (MMSE) at baseline and at Weeks 4, 8 and 12 (or cessation) after initiation of donepezil.
Caregivers' burden of nursing
We assessed the caregivers' burden of nursing prior to initiation of donepezil. Changes in the burden of care from baseline were graded using a four-point scale as follows: 1, ‘No burden’; 2, ‘Burden decreased’; 3, ‘Burden unchanged’; 4, ‘Burden increased’. Any nonevaluable data were recorded as such.
Clinicians recorded the presence or absence of any adverse events (including abnormal laboratory parameters) that occurred after donepezil administration: the name of the event, the date of onset, severity, use of donepezil, regimen, date of outcome determined, outcome, and causal relationship with donepezil.
For efficacy analysis based on changes in BPSD, we determined the ratio of patients in each of the three groups (improved, unchanged, or worsened) after ruling out patients not having any symptoms prior to treatment, and calculated 95% confidence intervals (CI). The presence or absence of medications (or concomitant drugs) was also examined; if other drugs were being used concomitantly, the class of the drug (e.g. major or minor tranquillizers, antidepressants, hypnotics) was stratified for interstrata comparison of efficacy. Stratified analysis was then performed in patients in whom BPSD was ‘improved’; those patients in whom BPSD was ‘unchanged’ or ‘worsened’ were defined as ‘non-improved’. In safety analysis, we obtained the number and rate of incidence of adverse drug reactions (ADRs) for which donepezil-related causality could not be ruled out. The number and rate of incidence of ADRs collected using Medical Dictionary for Regulatory Activities/J (MedDRA/J) (Ver. 6.1) (http://www.sjp.jp/~jmo_new2006/php/indexj.php) were classified by Preferred Term (PT) and System Organ Class (SOC). Significance was set at 5% (two-sided) and was used for each test unless specified otherwise; T-distributions were used to calculate CI.
Demographic characteristics of the patients
Table 2 lists the demographic characteristics of the 252 patients included in efficacy assessment. Overall, 66.7% of patients were female (mean age 78.0 years). Evidence of BPSD consisted of hallucinations/delusions in 161 patients (63.9%), wandering in 91 patients (36.1%), and aggression in 124 patients (49.2%). Medications for BPSD had been prescribed to 79 patients (31.3%) prior to the administration of donepezil. During the survey period, psychoactive treatments for BPSD were given to 85 patients (33.7%) and major tranquillizers were coadministered to 74 patients (29.4%). The mean duration of donepezil treatment was 83.2 days.
Table 2. Patient demographics (efficacy assessment population)
| Male||84 (33.3)|
| Female||168 (66.7)|
| 15–64||10 (4.0)|
| 65–84||191 (75.8)|
| ≥85||51 (20.2)|
| Outpatient||167 (66.3)|
| Inpatient||63 (25.0)|
| Outpatient→inpatient||8 (3.2)|
| Inpatient→outpatient||14 (5.6)|
|Severity of dementia|
| Mild||119 (47.2)|
| Moderate||133 (52.8)|
| Hallucinations/delusions||161 (63.9)|
| Wandering||91 (36.1)|
| Aggression||124 (49.2)|
|Medications for BPSD (given previously)|
| No||173 (68.7)|
| Yes||79 (31.3)|
| Major tranquillizers||69 (27.4)|
| Minor tranquillizers||4 (1.6)|
| Anti-depressants||9 (3.6)|
| Hypnotics||12 (4.8)|
| Others||3 (1.2)|
|Medications for BPSD (concomitant drugs)|
| No||167 (66.3)|
| Yes||85 (33.7)|
| Major tranquillizers||74 (29.4)|
| Minor tranquillizers||6 (2.4)|
| Antidepressants||7 (2.8)|
| Hypnotics||13 (5.2)|
| Others||6 (2.4)|
|Treatment duration (days)|
| ≤14||2 (0.8)|
| 15–28||6 (2.4)|
| 29–56||22 (8.7)|
| 57–84||47 (18.7)|
| 85–112||165 (65.5)|
| ≥113||10 (4.0)|
Changes in BPSD
After eliminating nonevaluable cases, the ratio of improved patients was defined as BPSD improvement rate; whereas that of worsened patients was defined as BPSD deterioration rate. Table 3 lists changes in BPSD and outcomes collected.
Table 3. Changes in behavioral and psychological symptoms of dementia
| 4 weeks||155||60||38.7 (31.0–46.9)||92||59.4 (51.2–67.2)||3||1.9 (0.4–5.6)|
| 8 weeks||141||79||56.0 (47.4–64.4)||62||44.0 (35.6–52.6)||0||0.0 (0.0–2.6)|
| 12 weeks||121||81||66.9 (57.8–75.2)||40||33.1 (24.8–42.2)||0||0 (0.0–3.0)|
| LOCF||158||95||60.1 (52.0–67.8)||61||38.6 (31.0–46.7)||2||1.3 (0.2–4.5)|
| 4 weeks||84||36||42.9 (32.1–54.1)||45||53.6 (42.4–64.5)||3||3.6 (0.7–10.1)|
| 8 weeks||76||40||52.6 (40.8–64.2)||32||42.1 (30.9–54.0)||4||5.3 (1.5–12.9)|
| 12 weeks||68||44||64.7 (52.2–75.9)||22||32.4 (21.5–44.8)||2||2.9 (0.4–10.2)|
| LOCF||89||53||59.6 (48.6–69.8)||33||37.1 (27.1–48.0)||3||3.4 (0.7–9.5)|
| 4 weeks||120||50||41.7 (32.7–51.0)||67||55.8 (46.5–64.9)||3||2.5 (0.5–7.1)|
| 8 weeks||110||61||55.5 (45.7–64.9)||45||40.9 (31.6–50.7)||4||3.6 (1.0–9.0)|
| 12 weeks||99||70||70.7 (60.7–79.4)||28||28.3 (19.7–38.2)||1||1.0 (0.0–5.5)|
| LOCF||122||80||65.6 (56.4–73.9)||40||32.8 (24.6–41.9)||2||1.6 (0.2–5.8)|
The improvement rate for BPSD at last-observation-carried-forward (LOCF) was 60.1% for hallucinations/delusions, 59.6% for wandering, and 65.6% for aggression. For each symptom, the longer the period of administration, the higher the improvement rate observed. The BPSD deterioration rates at LOCF were 1.3% for hallucinations/delusions, 3.4% for wandering, and 1.6% for aggression. Table 4 lists changes in BPSD at LOCF stratified according to the use or not of other drugs concomitantly.
Table 4. Changes in behavioral and psychological symptoms of dementia
| No medications for BPSD||105||68||64.8 (54.8–73.8)||36||34.3 (25.3–44.2)||1||1.0 (0.0–5.2)|
| Medications for BPSD||53||27||50.9 (36.8–64.9)||25||47.2 (33.3–61.4)||1||1.9 (0.0–10.1)|
| Major tranquillizers||45||24||53.3 (37.9–68.3)||20||44.4 (29.6–60.0)||1||2.2 (0.1–11.8)|
| Minor tranquillizers||3||2||66.7 (9.4–99.2)||1||33.3 (0.8–90.6)||0||0.0 (0.0–70.8)|
| Anti-depressants||6||2||33.3 (4.3–77.7)||4||66.7 (22.3–95.7)||0||0.0 (0.0–45.9)|
| Hypnotics||6||2||33.3 (4.3–77.7)||4||66.7 (22.3–95.7)||0||0.0 (0.0–45.9)|
| Others||4||3||75.0 (19.4–99.4)||1||25.0 (0.6–80.6)||0||0.0 (0.0–60.2)|
| No medications for BPSD||44||26||59.1 (43.2–73.7)||15||34.1 (20.5–49.9)||3||6.8 (1.4–18.7)|
| Medications for BPSD||45||27||60.0 (44.3–74.3)||18||40.0 (25.7–55.7)||0||0.0 (0.0–7.9)|
| Major tranquillizers||38||23||60.5 (43.4–76.0)||15||39.5 (24.0–56.6)||0||0.0 (0.0–9.3)|
| Minor tranquillizers||4||2||50.0 (6.8–93.2)||2||50.0 (6.8–93.2)||0||0.0 (0.0–60.2)|
| Anti-depressants||2||2||100.0 (15.8–100.0)||0||0.0 (0.0–84.2)||0||0.0 (0.0–84.2)|
| Hypnotics||9||5||55.6 (21.2–86.3)||4||44.4 (13.7–78.8)||0||0.0 (0.0–33.6)|
| Others||5||4||80.0 (28.4–99.5)||1||20.0 (0.5–71.6)||0||0.0 (0.0–52.2)|
| No medications for BPSD||79||55||69.6 (58.2–79.5)||23||29.1 (19.4–40.4)||1||1.3 (0.0–6.9)|
| Medications for BPSD||43||25||58.1 (42.1–73.0)||17||39.5 (25.0–55.6)||1||2.3 (0.1–12.3)|
| Major tranquillizers||41||25||61.0 (44.5–75.8)||15||36.6 (22.1–53.1)||1||2.4 (0.1–12.9)|
| Minor tranquillizers||5||3||60.0 (14.7–94.7)||2||40.0 (5.3–85.3)||0||0.0 (0.0–52.2)|
| Anti-depressants||1||0||0.0 (0.0–97.5)||1||100.0 (2.5–100.0)||0||0.0 (0.0–97.5)|
| Hypnotics||7||3||42.9 (9.9–81.6)||4||57.1 (18.4–90.1)||0||0.0 (0.0–41.0)|
| Others||3||2||66.7 (9.4–99.2)||1||33.3 (0.8–90.6)||0||0.0 (0.0–70.8)|
The BPSD improvement rates for hallucinations/delusions at LOCF were 50.9% for patients receiving psychotropics and 64.8% for those not on psychotropics. Improvement rates for wandering in patients with and without concomitant psychotropic medication were 60.0 and 59.1%, respectively, whereas improvement rates for aggression were 58.1 and 69.6%, respectively. In cases where concomitant medications were being adminsitered, 42.6% of patients with hallucinations/delusions, 57.8% of those with wandering, and 40.9% of those with aggression were hospitalized. These rate of hospitalization were higher than for patients not on concomitant medications. In addition, of those patients receiving concomitant medications, 87.0% of those being treated for hallucinations/delusions, 88.9% of those being treated for wandering, and 84.1% of those being treated for aggression had been given anti-BPSD medications (i.e. treatments given previously) before initiation of donepezil.
Testing of cognitive function
The HDS-R scores were significantly improved, from 13.9 ± 5.7 at baseline to 14.9 ± 6.4 at LOCF. In addition, examination of BPSD according to item indicated that HDS-R scores were significantly improved for patients with hallucinations/delusions (Table 5).
Table 5. Changes in Revised Hasegawa Dementia Scale (by symptom)
|All patients||96||13.9 ± 5.7||14.9 ± 6.4||0.2–1.8||0.018|
|Hallucinations/delusions||64||14.4 ± 5.5||15.5 ± 6.1||0.2–2.0||0.017|
|Wandering||36||10.7 ± 6.3||10.9 ± 6.3||−1.1–1.6||0.719|
|Aggression||42||15.0 ± 5.8||16.2 ± 6.3||0.0–2.5||0.053|
The MMSE scores were significantly improved, from 17.9 ± 4.5 at baseline to 19.2 ± 5.5 at LOCF. In addition, examination of BPSD according to item indicated that MMSE scores were significantly improved in patients with hallucinations/delusions (Table 6).
Table 6. Changes in Mini-Mental State Examination (according to symptom)
|All patients||41||17.9 ± 4.5||19.2 ± 5.5||0.2–2.5||0.022|
|Hallucinations/delusions||36||17.6 ± 4.2||19.2 ± 5.3||0.4–2.8||0.013|
|Wandering||13||15.2 ± 5.7||16.5 ± 6.3||−1.4–4.0||0.319|
|Aggression||21||17.2 ± 5.0||17.7 ± 5.1||−1.3–2.2||0.578|
We examined changes in cognitive function before and after donezepil treatment in patients in whom BPSD were deemed improved and not improved (Tables 7,8). Significant improvements in HDS-R and MMSE scores were found for patients whose hallucinations/delusions were improved. In addition, significant improvements were noted in HDS-R scores for patients whose aggression was improved. Moreover, there were significant differences in the changes in HDS-R scores between patients whose hallucinations/delusions or wandering were improved and patients whose these symptoms were not improved.
Table 7. Changes in behavioral and psychological symptoms of dementia and scores on the revised Hasegawa Dementia Scale
| Improved||38||13.4 ± 5.5||2.3 ± 3.3||1.2–3.4||P = 0.000||P = 0.001|
| Non-improved||27||15.9 ± 5.0||−0.7 ± 3.3||−2.0–0.6||P = 0.289|| |
| Improved||21||9.7 ± 6.3||1.7 ± 4.7||−0.6–3.9||P = 0.133||P = 0.041|
| Non-improved||18||11.4 ± 6.0||−1.1 ± 2.7||−2.6–0.3||P = 0.117|| |
| Improved||37||14.1 ± 6.0||1.8 ± 4.0||0.4–3.2||P = 0.014||P = 0.064|
| Non-improved||10||16.1 ± 4.8||−1.1 ± 3.3||−3.9–1.6||P = 0.369|| |
Table 8. Changes in behavioral and psychological symptoms of dementia and scores on the Mini-Mental State Examination
| Improved||24||18.1 ± 4.3||2.5 ± 3.7||0.9–4.0||P = 0.004||P = 0.061|
| Non-improved||11||16.5 ± 4.1||0.0 ± 2.9||−1.9–1.9||P = 1.000|| |
| Improved||10||14.9 ± 5.5||2.6 ± 4.3||−0.5–5.7||P = 0.088||P = 0.056|
| Non-improved||4||17.0 ± 6.3||−3.0 ± 2.0||−8.0–2.0||P = 0.122|| |
| Improved||14||16.7 ± 5.6||1.1 ± 4.3||−1.4–3.6||P = 0.341||P = 0.357|
| Non-improved||6||18.3 ± 4.0||−0.7 ± 2.6||−3.4–2.0||P = 0.555|| |
After excluding patients who posed ‘No burden’ to their caregivers before and after treatment, as well as nonevaluable cases, data for 222 patients were analysed for efficacy analysis. The analysis indicated that the burden on caregivers at LOCF was 3.6% for ‘No burden’ and 54.1% for ‘Burden decreased’, accounting for 57.7% when combined. However, ‘Burden increased’ for 4.5% of patients (Table 9).
Table 9. Caregivers' burden
|4 weeks||212||0||0.0 (0.0–1.7)||81||38.2 (31.6–45.1)||124||58.5 (51.5–65.2)||7||3.3 (1.3–6.7)|
|8 weeks||196||8||4.1 (1.8–7.9)||94||48.0 (38.2–60.6)||89||45.4 (38.3–52.7)||5||2.8 (0.8–5.9)|
|12 weeks||169||6||3.6 (1.3–7.6)||102||60.4 (42.5–67.8)||56||33.1 (26.1–40.8)||5||3.0 (1.0–6.8)|
|LOCF||222||8||3.6 (1.6–7.0)||120||54.1 (47.3–60.7)||84||37.8 (31.4–44.6)||10||4.5 (2.2–8.1)|
There was an increase in the ratio of ‘No burden’ plus ‘Burden decreased’ as the duration of donepezil administration increased, reaching 63.9% at Week 12.
We evaluated the burden on caregivers of patients whose BPSD was classified as ‘Improved’ and ‘Non-improved’ after administration of donepezil. The ratio of combined ‘No burden’ plus ‘Burden decreased’ (88.5–94.4%) was significantly higher for patients in whom symptoms were relieved compared with patients in whom no improvement in BPSD were noted (Table 10).
Table 10. Changes in behavioral and psychological symptoms of dementia and caregivers' burden
| Non-improved||60||10||(16.7)||42||(70.0)||8||(13.3)|| |
| Non-improved||35||6||(17.1)||26||(74.3)||3||(8.6)|| |
| Non-improved||42||7||(16.7)||31||(73.8)||4||(9.5)|| |
Adverse drug reactions
Thirty ADRs were collected from 23 of 289 patients, giving an incidence rate of 7.96% and Table 11 summarizes those ADRs that were noted to occur.
Table 11. Adverse drug reactions
|Blood and lymphatic system disorders|
| Anemia||2 (0.69)|
|Metabolism and nutrition disorders|
| Decreased appetite||1 (0.35)|
| Anorexia||1 (0.35)|
| Depression||1 (0.35)|
| Excitability||1 (0.35)|
| Aggression||1 (0.35)|
| Insomnia||2 (0.69)|
| Delusion||2 (0.69)|
|Nervous system disorders|
| Parkinson's disease||1 (0.35)|
| Somnolence||1 (0.35)|
| Tremor||1 (0.35)|
| Headache||1 (0.35)|
| Dizziness||2 (0.69)|
| Nausea||5 (1.73)|
| Stomach discomfort||1 (0.35)|
| Constipation||1 (0.35)|
| Liver disorder||1 (0.35)|
|General disorders and administration site conditions|
| Malaise||1 (0.35)|
| Gait abnormal||2 (0.69)|
| Blood cholesterol increased||1 (0.35)|
| Blood urea increased||1 (0.35)|
The major ADRs were five cases of upper abdominal discomfort (1.73%) and two each of anemia, insomnia, delusions, dizziness, and gait disorder (0.69%). Serious ADRs were one case each of anemia, anorexia, dizziness, upper abdominal discomfort, and gait disorder. Of these episodes, anorexia, dizziness, and upper abdominal discomfort were reported by the same patient.
In the present study, unknown ADRs that were expected from ‘Precautions of use’ revised on 1 May 2003 (in Japanese; see http://www.info.pmda.go.jp/go/pack/1190012C1020_1_15/) were not observed.
The results of the present study suggest that improvement rates (the ratio of ‘Improved’ patients judged by the clinicians) for hallucinations/delusions, wandering, and aggression at LOCF in patients receiving donepezil ranged between 59.6% and 65.6%. Approximately 60% of patients experienced relief for each symptom. This leads us to believe that donepezil may be a useful treatment not only for BPSD, but also for cognitive dysfunction. At LOCF, we assessed the caregivers' burden of nursing resulting in ‘No burden’ in 3.6% and ‘Burden decreased’ in 54.1%. When examining the caregivers' burden in patients who were classified as either improved or non-improved, the proportion of patients that presented ‘No burden’ or ‘Burden decreased’ (88.5–94.4%) was significantly higher for patients in whom symptom relief was observed compared with patients in whom no improvement in BPSD was observed. Thus, improvements in BPSD consequently led to a reduction in caregivers' burden. Conversely, BPSD deterioration rates (the ratio of ‘Worsened’ patients, as judged by the clinicians) at LOCF ranged from 1.3 to 3.4%, and 4.5% of caregivers were judged as having an increased burden of care. Therefore, the results indicate that there is little risk that donepezil will unduly stimulate the neuropsychiatric status of AD patients by aggravating BPSD and increasing the nursing burden on caregivers.
In overseas research, Feldman et al.2 and Gauthier et al.3 have conducted placebo-controlled double-blind comparative trials in patients with moderate to severe AD. They reported that donepezil-treated groups yielded more significant improvements in total scores on the 12-item Neuropsychiatric Inventory (NPI) compared with baseline and placebo-treated groups. From symptom-based observations, there was a significant difference observed in depression/dysphoria, anxiety, and apathy between donepezil- and placebo-treated groups. Furthermore, Gauthier et al.4 attempted a partial statistical analysis of patients with moderate AD and suggested that total scores on the NPI were significantly different between donepezil- and placebo-treated groups. For each symptom (delusions, apathy, and aberrant behavior), there was a significant difference between donepezil- and placebo-treated patients. Meanwhile, in Japan, after the market launch of donepezil, many clinical studies reported the therapeutic benefits of donepezil in treating BPSD. Hori et al.5 reported that donepezil improved hallucinations/delusions in patients with AD. Tanigawa et al.6,7 reported that agitation and paranoid delusions were alleviated with concomitant donepezil therapy; in addition, wandering, persecutory delusion of belongings being stolen, and rage were markedly relived by donepezil monotherapy. These findings support the notion that donepezil is effective in the treatment of BPSD.
The 2002 Therapeutic Guidelines for Dementia published by the Japanese Society of Neurology state:
BPSD should be clearly defined based on non-pharmacotherapies including the well-arranged therapeutic environment for BPSD as much as possible. Currently, pharmacotherapy is the first choice for delirium, depressive condition/depression, and sleep disturbance. Neuroleptic agents are usually indicated for hallucinations/delusions, aggression, and excessive hyperactivity.8
In the present survey, we primarily compared the efficacy of donepezil in alleviating BPSD between patients with or without concomitant psychotropic medication. In those patients being treated with psychotropic medication, we further performed a stratified analysis to compare the efficacy of donepezil depending on the type of psychotropic medication being administered (major or minor tranquillizers, antidepressants, and hypnotics).
There was no difference observed in wandering between patients regardless of whether they were on other psychotropic medications, including major tranquillizers; however, there was a higher rate of improvement in hallucinations/delusions and aggression in patients being given concomitant psychotropics. Actual prescriptions in clinical settings revealed that patients who had not received major tranquillizers or other psychotropics prior to this survey were given donepezil monotherapy, whereas those who had already been on other psychotropic agents were administered donepezil as an additional treatment. As a whole, a significant improvement in cognitive function was observed in HDS-R and MMSE scores of all patients. When data were examined according to the presence or absence of BPSD, hallucinations/delusions were significantly improved in HDS-R and MMSE scores. Significant changes in wandering and aggression were not detected and this may be due to an insufficient number of patients analyzed. From the changes in BPSD and pre- and post-treatment changes in cognitive function observed, improved patients tended to show positive outcomes and greater mean changes in cognitive function regarding almost all BPSD. In contrast, non-improved patients tended to show deterioration of BPSD. Especially in terms of changes in HDS-R scores, there was a significant difference between improved and non-improved patients with hallucinations/delusions and wandering.
In the present survey, ADRs were observed to occur in 7.96% of patients. The major episodes were similar to those in previous post-marketing surveillance in Japan. Neither unknown ADRs nor foreseeable factors affecting the onset of ADRs were detected. Therefore, the results of our investigation raised no safety concerns.
There is, however, the results of the present survey should be intepreted with caution. Because we did not have a concurrent control group, we cannot rule out an interactive relationship between the efficacy of donepezil and the natural course of disease, as well as possible influence(s) of other medications.
Our post-marketing survey suggests that donepezil can be expected to be effective not only in the treatment of cognitive dysfunction, but also for BPSD. The clinical benefits of donepezil treatment reduced caregivers' burden among approximately 60% of AD patients, whereas donepezil itself was unlikely to cause a deterioration in BPSD, which would result in a heavier burden on caregivers, by excessively stimulating the neuropsychiatric condition of AD patients.