Abstract

Background

Since 2005, regulatory agencies have repeatedly warned of the increased risk of mortality associated with off-label antipsychotic use in elderly patients. The aim of this study was to investigate the use of antipsychotic drugs in elderly Japanese outpatients with Alzheimer’s disease seen in ambulatory practice.

Methods

This retrospective drug utilization study was conducted using a prescription database from community pharmacies across Japan. Among elderly outpatients aged 65 years or older who started new donepezil treatment, the proportion and time trend of antipsychotic use, daily dose, combination use, and duration of receiving prescriptions for antipsychotic agents were investigated.

Results

Between February 2007 and March 2009, a total of 13,454 patients were prescribed donepezil, of these 1,195 (8.9%) were prescribed antipsychotics for the first time, which were predominantly atypical agents. No significant changes in monthly prescription trends for total and atypical antipsychotics were observed. Among patients receiving antipsychotics, 126 (10.5%) were prescribed multiple antipsychotics; 37 (3.7%) were prescribed a daily dose of antipsychotics exceeding the American Psychiatric Association recommendations; and 496 (44.2%) received the prescription for more than three months.

Conclusions

Antipsychotics continue to be prescribed to elderly outpatients with Alzheimer’s disease in Japan. This population accounts for the majority of elderly subjects requiring nursing care in Japan. Atypical agents predominated throughout the study period. Some patients received antipsychotic polypharmacy, and prolonged use of antipsychotics was prevalent. Given the reported increased risk of mortality in elderly patients associated with the long-term use of antipsychotics, these results highlight the ongoing need to monitor the rational use of antipsychotics in Japan.

Key words Alzheimer’s disease, Antipsychotics, Elderly, Geriatric, Japanese, Drug utilization.

Author and Article Information

Author info
1 Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan
2 Clinical Research Coordinator Course, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan
3 Department of Medical Ethics, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan

RecievedSep 24 2013　　AcceptedJan 28 2014　　PublishedFeb 5 2014

CitationUrushihara H, Kobayashi S, Honjo Y, Kosugi S, Kawakami K (2014) Utilization of antipsychotic drugs in elderly patients with Alzheimer’s disease seen in ambulatory practice in Japan. Science Postprint 1(1): e00014. doi:10.14340/spp.2014.01C0003

Copyright©2014 The Authors. Science Postprint published by General Healthcare Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 2.1 Japan (CC BY-NC-ND 2.1 JP) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

FundingThis study was supported by the Special Coordination Funds Promoting Science and Technology for Special Training Course of Genetic Counselors and Clinical Research Coordinators, sponsored by the Ministry of Education, Culture, Sports, Science and Technology (no grant number provided).
The funder had no role in study design, collection, analysis and interpretation of data, decision to publish, or preparation of the manuscript.

Competing interestsKK received paid consultancy from Novartis K.K., and Otsuka Pharmaceuticals Co., Ltd.
HU received paid consultancy from Eli Lilly Japan.
The other authors declare no relevant conflict of interest.

Ethics statementBecause the pharmacy claims database investigated in the present study were retrieved from automated electronic databases and de-identified before provision to the study group, the study was exempt from obtaining informed consent from individual patients according to the local ethical guideline for epidemiological research. This study and the waiver of informed consent were approved by the Kyoto University Graduate School and Faculty of Medicine, Ethics Committee (application No.: E-774).

Corresponding authorKoji Kawakami
AddressDepartment of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University
Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
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Introduction

Alzheimer’s disease (AD) is one of the major etiologies of dementia, which accounts for approximately 60% of dementia 1. In the middle or later stage of AD, behavioral and psychological symptoms of dementia (BPSD) are developed, and support and long term care for these elderly with AD who experience BPSD is one of the most serious social problems facing aging countries.
In Japan, close to 30 million people were over 65 years old as of October 2011, accounting for 23.3% of the population, the highest percentage in the world 2. Over 3 million Japanese were reported to suffer from dementia in 2012, and this number is expected to increase as Japanese society ages 3. In Japan, close to 80% of elderly with certified long-term care needs reside at their home and are provided with nursing care services 4.
The only medicinal product approved for the treatment of AD in Japan was donepezil, prior to the approval of galantamin and memantine in January 2011. Nevertheless, typical antipsychotics, such as haloperidol and chlorpromazine, were frequently used off-label to control BPSD. While these typical antipsychotics are associated with particular adverse effects, such as extrapyramidal symptoms, atypical antipsychotics were reported to be safer 5, and their off-label prescription for elderly dementia patients has increased significantly 6, 7.
Against this background, a public health advisory issued on April 11, 2005 by the U.S. Food and Drug Administration (FDA) warned of an increased risk of death associated with the use of atypical antipsychotics in elderly patients with dementia, and a boxed warning was added to their labeling describing this risk and noting that these drugs were not approved for this indication 8. In August 2005, the Japanese Ministry of Health, Labor, and Welfare (MHLW) issued notifications of a package insert revision for atypical antipsychotics to include increased mortality when used off-label in elderly patients with dementia 9. The FDA then extended this boxed warning to all antipsychotics, including typical antipsychotics, in June 2008 10, and the MHLW followed suit in January 2009 (Table S1) 11. This excess mortality risk was reported to persist for 180 days after initial administration of antipsychotics, with a higher risk for typical than atypical agents regardless of place of residence 12, 13. Nevertheless, limited efficacy in BPSD control has been shown for some antipsychotics, and the use of antipsychotics in elderly patients with dementia remains controversial 12, 14, 15.
Despite these regulatory advisories and their implications for rational use, the use of antipsychotics in Japanese patients with dementia has not been systematically reported. Here, we conducted a drug utilization study of antipsychotic drugs among elderly outpatients with AD in Japan with a focus on drug class, time trend, treatment duration, and dosages used.

Methods

Data source

We consulted a database of prescriptions filled at 451 community pharmacies operated by two community pharmacy chains, which account for approximately 1.0% of the total number of dispensing pharmacies in Japan 16. Most of these dispensing pharmacies were located in front of clinics and/or hospitals. This database was the largest and only accessible pharmacy database available for epidemiological research at that time and the database had the same age and gender distribution as national patient statistics 17. These pharmacies fill approximately 10 million prescriptions per year, accounting for approximately 1.4% of the total yearly outpatient prescriptions in Japan 17. The database contains a patient identification number, age, gender, date of dispensing, name and code of the prescription drug, formulation, dosage, daily dose, and dosing days.

AD patients studied

At the time of the study, donepezil was the only drug approved for the treatment of AD in Japan. Under Japan’s universal national health insurance reimbursement scheme, donepezil is immediately available for patients after the diagnosis by a registered health insurance doctor and prescribed because the patients or their caregiver usually desire medications due to low copayment, especially for the elderly, even when AD signs and symptoms are mild. We therefore considered the first prescription of donepezil to indicate a diagnosis of AD. Prescription data were obtained from the two pharmacy chains for the period of August 2006 to March 2009. 21,901 patients aged ≥ 65 years and prescribed donepezil were screened (Figure 1). The 8,130 patients who had records of receiving either donepezil or antipsychotics prior to February 2007 were excluded, ensuring a donepezil- and antipsychotics-free eligibility period of at least 6 months for each remaining patient based on the pharmacy records (Figure S1) 18. Initiation of donepezil use was identified by the first prescription of donepezil from February 2007 and March 2009, subsequent to the eligibility period 19. 317 patients receiving antipsychotic prescriptions prior to the first donepezil prescription were excluded to reduce possible contamination of antipsychotic use for schizophrenia treatment. Five patients prescribed antipsychotics concomitantly with anticancer agents or narcotic analgesics were not counted as antipsychotic users in this study as these prescriptions were likely for emetic control rather than psychotropic use.
Because the pharmacy claims database investigated in the present study were retrieved from automated electronic databases and de-identified before provision to the study group, the study was exempt from obtaining informed consent from individual patients according to the local ethical guideline for epidemiological research. This study and the waiver of informed consent were approved by the Kyoto University Graduate School and Faculty of Medicine, Ethics Committee (application No.: E-774).

Antipsychotic drugs administrated

Antipsychotic drugs and drug classes used for analysis are shown in Table S1. The following drugs were classified as “atypical antipsychotics”: risperidone, perospirone, quetiapine, olanzapine, aripiprazole, and blonanserin. Of note, blonanserin has only been marketed in Japan since April 2008, which occurred after the beginning of the study period. All other antipsychotic drugs were classified as ‘typical antipsychotics’. Although sulpiride is sometimes prescribed as an antipsychotic, it was excluded from the study because it is often used to treat depression and gastroduodenal ulcers.

Descriptive data

Cumulative incidence of initial antipsychotics prescription was calculated by dividing the number of incident users of antipsychotics by the number of incident users of donepezil. The incidence rate of initial antipsychotics use was calculated after excluding patients prescribed antipsychotics on the same day as first donepezil prescription, as follows: the number of incident users of antipsychotics was divided by the total at-risk period of antipsychotics use starting with the first donepezil prescription in the incident users of donepezil. For antipsychotics users, the at-risk period ended with the initial prescription date of any antipsychotic. For non-users, the at-risk period ended with the end of the observation period or the last visit date to the pharmacy, whichever occurred earlier (Figure S1). Monthly trend of antipsychotics use was presented by a percentage of the monthly visits mentioning antipsychotics among all the visits made by the incident donepezil users. Combination use of antipsychotics was defined as a prescription of more than one antipsychotic drug filled on the same day. The duration of a single course of continuous antipsychotic prescription was calculated from the dispensing date, number of dosing days, and prescription interval for each patient. A continuous prescription course was regarded as terminated if there was a break of ≥ 14 days without any antipsychotic usage. The prescribed daily dose for each antipsychotic drug was compared with the American Psychiatric Association (APA) recommended maximum dose for the treatment of psychosis and agitation 20. This was the only guideline available which provided reference dose ranges of antipsychotics for off-label BPSD treatment, and was referenced in the guidelines for dementia treatment in Japan 21. The daily dose and duration of continuous prescription were summarized using descriptive statistics.

Statistical test

We used regression analysis with segmented relationship to study whether the monthly trend of antipsychotic prescriptions changed during the observation period 22. A segmented relationship between the mean response µ and the time point variable Z, for observation i = 1, 2,･･･, n, was modeled with a Generalized Linear Model by adding in the linear predictor the following terms: β₁z_i +β₂(z_i -φ)₊; where (z_i -φ)₊ = (z_i -φ) × I (z_i >φ) and I (･) is the indicator function equal to one when the statement is true 23. Note that β₁ is the left slope, β₂ is the difference-in-slope and φ is the breakpoint (b.p.). If the breakpoint does not exist, the difference-in-slope β₂ has to be zero. The R package for segmented regression model, segmented, included the Davies test to test the null hypothesis H₀: β₂ (φ) = 0 for given a breakpointφ. The best breakpoint was estimated among a given number of breakpoints within the range of Z. In this analysis, a binomial link function was applied to the GLM and 24 breakpoints were submitted to the Davies test during the 26-month period of observation, after excluding the month 1 (February 2007) and 26 (March 2009).
Statistical analysis was performed with SPSS 17 for Windows (SPSS Inc., Chicago, IL, USA) and the R package ‘Segmented’ of R var. 2.15.2 at a two-sided significant α level of 0.05.

Results

From February 2007 to March 2009, 13,454 incident donepezil users were identified, of whom 1,195 (8.9%) were prescribed any antipsychotics (Figure 1). Age and gender proportions of all patients receiving donepezil (age, mean ± SD [max]: 80.5 ± 6.3 [105], male: 35.3%) were almost identical to those of antipsychotics incident users among the donepezil patients (age: 80.3 ± 6.8 [100], male: 37.8%). After excluding 3,081 patients without more than two visits to the pharmacy, the remaining 10,373 elderly outpatients were followed for mean (± SD) duration of 245 ± 209 days, with a cumulative total of up to 6,960 patient-years (Figure 1 a). Among the 1,195 new users of antipsychotics, 668 patients (55.9%) were first prescribed donepezil and antipsychotics on the same day, while the remaining 527 antipsychotics users had mean (± SD) duration of 168 ± 169 days from the first prescription of donepezil to the first prescription of antipsychotics. Total at-risk period of new antipsychotic prescription in 9,873 donepezil users free of antipsychotics at enrollment was 6,556 patient-years, after excluding the 500 donepezil users who were followed for more than one day but who were prescribed antipsychotics at the same time on the first donepezil date (Figure 1 b). Thus, the incidence rate of antipsychotic prescriptions among these donepezil users was 80.4 (95% confidence interval: 73.7 – 87.5) per 1,000 patient-years.

Figure 1Patient disposition for a retrospective pharmacy database study of antipsychotics drug utilization among elderly patients with Alzheimer’s disease

(a) and (b) indicate patients for calculation of cumulative follow-up periods.
(b) included 527 patients for calculation of incidence rate of antipsychotics prescription after initial donepezil prescription.

A large majority of patients received atypical antipsychotics (88.3%; Table 1), most frequently risperidone (50.0%), followed by quetiapine (34.0%). Relatively few patients were prescribed typical antipsychotics (17.2%). The percentages of monthly visits for antipsychotics among the donepezil users was stable at around 8% throughout the study period with a low percentage of visits mentioning typical agents (Figure 2). The segmented regression model indicated that no significant b.p. for prescription trends of total and atypical antipsychotics existed (best b.p. estimated at June 2007, p = 0.205 for total and 0.584 for atypical, respectively); however, a significant b.p. in July 2007 for prescription trends of typical antipsychotics was identified (p = 0.015) subsequent to a significant initial increase (p = 0.009).

Figure 2Monthly rate of antipsychotics prescriptions in elderly patients with Alzheimer’s disease using donepezil

Of the 126 patients with antipsychotics polypharmacy (10.5% of all antipsychotics users), 117 patients were prescribed two antipsychotics simultaneously, 8 were prescribed three, and 1 was prescribed four. Thirty-seven patients (3.7%) were prescribed a dose of antipsychotics that exceeded the recommended maximum APA guideline dose (Table 2). One patient was prescribed aripiprazole at a daily dose of 36 mg, which exceeded the approved maximum daily dose of 30 mg for schizophrenia treatment given in the Japanese package insert. Mean (± SD) duration of continuous antipsychotic administration was 144 ± 166 days. Almost half (44.2%) of antipsychotics patients were prescribed antipsychotics for more than 90 days (Table 3).

Discussion

In this study, we evaluated the utilization of antipsychotics among elderly outpatients with AD using a large-scale pharmacy prescription database in ambulatory practice in Japan. The cumulative incidence of antipsychotics usage among elderly patients with AD was estimated at 9%, and prolonged use of more than three months was prevalent during the period of February 2007 to Mar 2009. New prescriptions of antipsychotics were constant, with atypical agents dominant, despite repeated warnings against antipsychotics use in elderly patients by the U.S. and Japanese authorities since 2005.
We found that the cumulative incidence of antipsychotics use in elderly outpatients with AD was not as high as that found and expected in elderly residents of nursing homes. Few studies on antipsychotics utilization among the elderly in outpatient settings have appeared; a US study reported that 11.5% of visits mentioned atypical antipsychotics 24, close to our finding. In addition, a UK study using a general practitioners database reported a prescribing rate of as low as 17.7% 25. According to the 2009 statistics in Japan, 78.8% of elderly persons who received nursing care services use daily home care or day care facilities without a medical facility and therefore see practitioners as outpatients, however, the remaining 21.1% were institutionalized in nursing care homes with permanent medical facilities, of which the elderly in needed support condition were rarely admitted 4. Thus, our results showing comparatively low rates of antipsychotics prescriptions in an ambulatory setting should be clearly differentiated from the other previous studies reporting a high prevalence of antipsychotics use among the elderly residents of nursing homes 26, 27. Additionally, we believe that our patients, as a whole, likely represent mild to moderate disease severity due to the following reasons; the attending physicians considered that these patients were in need of pharmacological interventions; more than half of incident antipsychotics users were prescribed antipsychotics on the same day as they started treatment with donepezil; and the other incident donepezil patients started antipsychotics within a relatively short period. The reported prevalence of psychotic symptoms (delusions or hallucinations) in community-dwelling patients with AD varies from 12% to 74% (median, 41%) 28, and agitation/aggression is reported in 24% of patients with dementia who live in the community 29. Antipsychotics are not the first choice of BPSD treatment in Japan according to the recommendations of the Japanese guidelines for dementia treatment 30. Because diagnosis was not available, we used drug prescriptions as a surrogate of disease diagnosis, and underestimation is likely to occur when no medication is given despite the presence of a disease 18. Additionally, the present study focused on the new use of antipsychotics among pharmacy outpatients with an AD diagnosis, which accounts for only about half of dementia patients 31 in contrast to many previous reports involved elderly patients with any type of dementia diagnosis. Further, to minimize the risk of contamination with schizophrenia treatment, we excluded patients prescribed antipsychotics before donepezil. Thus, our estimate of the incidence rate of antipsychotics use is likely lower than the estimates of BPSD development among elderly patients with dementia.
Despite the 2008 FDA warning and subsequent 2009 Japanese package insert changes, we found no marked change in time trend of antipsychotic prescriptions among elderly outpatients with AD, except for typical agents 10, 11. The initial significant rise in the prescription rate of typical antipsychotics is likely an artifact due to the small sample size at risk during the early phase of the present study that incorporated an incident user design. The FDA warning was disseminated in Japanese on July 24, 2008 as an official “Overseas Drug Safety Information” report provided by the National Institute of Health Science, a distinct governmental agency within the Pharmaceuticals and Medical Devices Agency which has primary responsibility for domestic communications on drug safety 32. The issuing of this FDA advisory was not reported by any newspaper in Japan, even after the subsequent revision of the Japanese package inserts of all typical antipsychotics to include this elevated mortality risk in January 2009 (Table S1), indicating low awareness in the Japanese society 11, 33. The mortality risk was placed in the section titled ‘other precautions’ at the very end of the precautions list for these agents; although, the Japanese regulation required practitioners to be notified of these revisions 34. Previous studies suggest that publicity might strongly influence the effectiveness of regulatory advisories, indicating that concerted efforts with mass media and prompt international cooperation between regulatory agencies might facilitate and encourage their implementation 17, 35, 36. However, our evaluation period might not have allowed conclusive determination of the effects of the January 2009 advisory in Japan. A second possibility might explain the lack of change in prescription trends is that the risks associated with antipsychotics use in the elderly were already widely acknowledged by the Japanese prescribing community during the study period. Therefore only the minimum number of patients actually requiring treatment might have been treated with antipsychotics.
Consistent with reports from the U.S. and Canada 7, 36, atypical antipsychotics predominated over typical antipsychotics among our pharmacy outpatients throughout the study, with risperidone as first choice, followed by quetiapine. A U.S. Veterans Health Administration registry study from May 2004 to September 2008 also reported the predominance of atypical over typical antipsychotics, with quetiapine and risperidone again being the top two choices 37. Several reports may offer clues to this treatment preference: efficacy in the treatment of BPSD reportedly varies among antipsychotics, including haloperidol, risperidone, aripiprazol, and olanzapine, but only quetiapine failed to show statistical superiority in efficacy over placebo 14, 15. Further, this predominance of risperidone in elderly Japanese may be explained with regard to safety, given that quetiapine and olanzapine are contraindicated in patients with diabetes mellitus owing to their well-known effect of inducing abnormal blood glucose levels 38, 39.
We found that a small number of antipsychotics users received a daily dose exceeding the APA guideline and that the mean doses of risperidone, quetiapine, and olanzapine in Japanese patients were strikingly similar to those reported in the US Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer’s Disease (CATIE-AD) study, in which doses were adjusted as needed 15, 20. Given that the antipsychotic doses used were lower than the approved dose ranges for schizophrenia in Japan and that the APA guideline was referenced in the recently published Japanese guidelines for the treatment of dementia, we suggest that the APA guidelines influenced the prescription practices of Japanese practitioners for BPSD treatment 21, 30, 40. Further, a portion of our AD patients were prescribed multiple concurrent antipsychotics. Previous studies found that the use of multiple antipsychotics for psychotic disorders had increased and was associated with an increased risk of adverse events and longer inpatient stays without apparent clinical benefit 41, 42, and regular review of the risks and benefits of antipsychotics treatment in AD patients with trial discontinuation (e.g., at 3- to 6-month intervals) is accordingly recommended 20, 43-45. In the present study, however, about half of the antipsychotics treatments continued for more than three months, implying that prolonged use is prevalent in Japanese outpatients with AD, as was similarly seen in a population-based study in the UK 25. The Japanese psychiatric community should be clearly advised of the need for close monitoring and careful consideration of the benefit-risk balance when considering continued long-term antipsychotic drug use or when prescribing multiple antipsychotics in elderly patients.
Several limitations of the present study warrant mention. First, data were not derived from a random sample of prescriptions, as the study pharmacies were heterogeneously located around Japan 17. However, since the study database was large, covering approximately 10 million pharmacy prescriptions per year throughout Japan, and the age and gender distribution of patients matched data from a national patient survey, we believe that the data from the study database are to some extent generalizable to the greater Japanese ambulatory setting 17, 46. Second, our assumption of AD was based solely on prescription records from the study pharmacy database, not diagnostic information, and therefore the potential for misclassification was unavoidable. Donepezil was also likely to be used for treatments of other types of dementia, such as dementia with Lewy bodies and vascular type; this misclassification is unlikely to be serious, however, given that these antipsychotics are also likely to be used off-label for other types of dementia. Lastly, follow-up of patients with prescription records in the study pharmacy database was likely incomplete in terms of continuity, as data for prescriptions filled at other pharmacies or prescribing medical institutions were inaccessible. We believe that this incompleteness likely had little impact on our estimates for elderly outpatients requiring long-term care, however, for the following reasons: (a) donepezil and antipsychotics are usually prescribed in the same clinical practice for the same treatment purpose and a single prescription is filled at a single pharmacy; (b) elderly outpatients and their care-givers (frequently only care-givers visit pharmacies to fill prescriptions) can be assumed to seek fewer opportunities to change their medical institutions and pharmacies (excluding definitive but infrequent reasons such as moving and hospitalization) because of the generally uniform, standardized medical services provided around Japan; and (c) mean follow-up of eight months per patient at a pharmacy appears long enough to cover the relatively short period to the start of antipsychotics. Nevertheless, some misclassification due to this incompleteness appears unavoidable. Any interpretation of our study results should take these limitations into careful consideration.

Conclusions

Antipsychotics continue to be prescribed to elderly Japanese patients with AD. Several patients were found to have been prescribed combinations of antipsychotics, and prolonged use was prevalent, both of which are negatively implicated in the risk-benefit balance of antipsychotics use in elderly patients. These results highlight the ongoing need to monitor the rational use of antipsychotics in treating elderly dementia patients and the need to seek less harmful treatments for BPSD.

Acknowledgments

This study was supported by a grant from the Japan Science and Technology Agency (Special Coordination Funds for Promoting Science and Technology). Dr Urushihara is a paid consultant for Eli Lilly Japan. The remaining authors have no commercial conflicts of interest that would bear on the present paper.
We acknowledge Ms. Yuko Doi and Mr. Yosuke Fujii, Ain Pharmaciez Inc., and Mr. Masaru Arai and Mr. Toshiyuki Matsunaga, Kraft Inc., for the generous provision of pharmacy claims data.

Author contributions

Conceived and designed the experiments: Urushihara H, Kobayashi S, Honjo Y, Kawakami K
Analyzed the data: Urushihara H, Kobayashi S
Wrote the paper: Urushihara H, Kobayashi S
Acquisition of data: Urushihara H
Interpreted the data: Urushihara H, Kobayashi S, Honjo Y, Kosugi S, Kawakami K
Critical revision of the manuscript for important intellectual content: Honjo Y, Kosugi S, Kawakami K
Approved the manuscript: Urushihara H, Kobayashi S, Honjo Y, Kosugi S, Kawakami K

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Supplemental Data

Supplemental figure 1Scheme for at-risk period of incident antipsychotics prescriptions among eligible donepezil users.