Use of Psychotropic Drugs and Drugs with Anticholinergic Properties

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from PEER REVIEW HISTORY

BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf) and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below.

ARTICLE DETAILS

TITLE (PROVISIONAL) Use of psychotropic drugs and drugs with anticholinergic properties among residents with dementia in intermediate care facilities for older adults in Japan: a cohort study AUTHORS Hamada, Shota; Kojima, T; Hattori, Yukari; Maruoka, Hiroshi; Ishii, Shinya; Okochi, Jiro; Akishita, Masahiro

VERSION 1 – REVIEW

REVIEWER Hélène Verdoux University of Bordeaux France REVIEW RETURNED 18-Nov-2020

GENERAL COMMENTS It is of great interest to explore the prescribing practice of drugs with anticholinergic properties in elderly persons, considering the risks associated with exposure to high anticholinergic load, especially in persons presenting with dementia. It is also of interest to investigate this issue in different countries with different organizations of care for these persons. The present study as several strengths particularly regarding deprescribing of drugs with deleterious side effects in elderly persons after admission in the http://bmjopen.bmj.com/ Roken services. Unfortunately, this interesting point is not sufficiently developed. The present study is hampered by several methodological drawbacks that should be further addressed by the authors.

In the highlights section: please give the spelled-out form of the acronym NH/LTCFs.

on September 30, 2021 by guest. Protected copyright. The aims of the study are unclear and do not match with the analyses reported in the manuscript. The most interesting part of the study is related to change of prescription over the 1st two months after admission. This issue is not mentioned in the aim section.

The organization of Roken has to be further explained for international readers : are they private or public structures ? Which proportion of elderly persons are managed in these structures in Japan ? What is the mean age at admission ? What is the organization of medical care i.e. who are the practitioners in charge of medication prescribing ? Are the drugs free of charge the patients ? It is also unclear for me whether the persons are living in the Roken as they are described as “resident” but it is also mentioned that the aim of the Roken is to improve functioning to live at home. Are persons leaving the Roken once included, and if yes, what is the mean duration of stay ?

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from The rationale and method used to identify the sample of Roken under study is unclear. Why only 368 Roken were included ? How many Roken were existing in Japan in 2005 (3,598? ) i.e. which proportion of the total number of Roken is included in the present study ?

The method used to collect information on prescribed drugs is not sufficiently detailed, especially for drugs prescribed at admission. How was obtained this information ? By whom ? From which source ?

Which classification was used to categorize the psychotropic drugs ? The list provided is not sufficient, the categories have to be defined according to international classifications (ATC for instance). It is really difficult to understand why mood stabilizers were not included in a study on psychotrotric drugs. This issue is problematic considering the case definition of dementia, as persons presenting with severe mental illness such as bipolar disorder or schizophrenia may be diagnosed as presenting with dementia, and these persons are frequently treated by mood stabilizers (lithium or anticonvulsants).

Regarding antipsychotics, please use the terms 1st and 2nd generation antipsychotics instead of typical and atypical, and also describe which drugs are included in these 2 categories as the list of marketed antipsychotics is highly variable from one country to another ; sulpiride is not considered as a 2nd generation antipsychotics in the literature, amisulpride is the only benzamide drug categorized as 2nd generation.

The definition of psychotropic polypharmacy is also problematic regarding the issue explored in the present study. Polypharmacy

may also be related to the co-prescription of several drugs from http://bmjopen.bmj.com/ the same pharmacological category for instance 2 antipsychotics or 2 antidepressants.

The method used to asses anticholinergic activity is questionable. It is true that various scales are available, but some of them are more reliable than others. It is acknowledged that the most relevant are those assessing an anticholinergic score : see for instance Salahudeen, M. S., Duffull, S. B. & Nishtala, P. S. (2015). Anticholinergic burden quantified by anticholinergic risk scales and on September 30, 2021 by guest. Protected copyright. adverse outcomes in older people: a systematic review. BMC Geriatrics 15, 31 ; Duran, C. E., Azermai, M. & Vander Stichele, R. H. (2013). Systematic review of anticholinergic risk scales in older adults. Eur J Clin Pharmacol 69, 1485-96. Hence, the findings of the present study regarding this variable should be considered with cautious.

The comparisons of the characteristics of patients according to the severity of dementia are of little interest in the present study as they are out of the scope of the objectives (which have to be better defined as already mentioned). These findings have to be suppressed.

Also regarding the statistical analyses, the method used to explore the most interesting issue related to changes in prescription after admission has to be revised. This point has to be developed, and the authors should consider use of multivariate rather than univariate analyses to explore this issue. It is much more

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from interesting to explore the factors associated with change in prescription (especially deprescribing of drugs with cognitive side effects) rather than with prescriptions at one point.

The section results is poorly structured and poorly presented. Once again, the comparison of prescription according to the severity of dementia is of little interest considering the limited validity of these categories. Table 2 has hence to be drastically modified and focused on the temporal evolution of prescriptions, using multivariate analyses, with severity of dementia as an adjustment variable.

More details should be given on the type of prescribed antipsychotics. It is useless to distinguish 1st and 2nd generation antipsychotics in the method if these categories are never used in the analyses and the results.

Yokukansan, a traditional Japanese Kampo medicine, is presented in the result section, and should be presented first in the method section with further explanations on this treatment.

The discussion mostly repeats the information already given in the result section. Once again, the most interesting issue of this study is related to deprescribing of drugs with deleterious side effects after admission in Roken i.e. in the health service specialized in geriatric care. This issue is much more interesting for the international readers than the description of prescribing practices in the elderly population.

REVIEWER Gerlach, Lauren B University of Michigan REVIEW RETURNED 27-Jan-2021

http://bmjopen.bmj.com/ GENERAL COMMENTS In this study the authors evaluated the prevalence of psychotropic and anticholinergic medication prescribing to residents in long- term care facilities (Roken) in Japan. Use of potentially inappropriate medications among nursing home residents and residents with dementia is a major issue given the risk of medication related harms. This study provides useful information regarding psychotropic and anticholinergic medication prevalence

within Roken as well as factors associated with prescribing. The on September 30, 2021 by guest. Protected copyright. manuscript could be strengthened through the following revisions.

Major Issues:

Introduction (Page 6, Lines 19-26): The Introduction overall would be strengthened by providing a little more information regarding Roken for International readers to best place this type of care facility in context. From the description provided, Roken may sound more similar to a subacute rehabilitation facility in the U.S., rather than a long-term care nursing home where the majority of previous work regarding psychotropic prescribing has been performed.

Methods: Overall it would be helpful to provide more information about who are the respondents filling out the surveys and how they were selected. Are these families of patients with dementia, facility staff caring for the patient, or patients themselves in some cases? A description of how it was determined who would fill out

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from the survey would be helpful as well as the breakdown of respondents for the information presented here (if available).

Discussion: -It would be helpful to provide some information regarding potential regulatory pressures or initiatives to reduce antipsychotic prescribing in Japan. For instance, in the U.S. nursing home antipsychotic prescribing rates publicly reported and impact nursing facilities ratings through a Five Star Rating System. Is there similar public reporting or regulatory pressures/initiatives to drive down antipsychotic prescribing in Roken? This information would be helpful for readers to put in context the various factors that may be influencing prescribing.

Minor Issues:

Methods: - Were medications only captured by the results of the survey or also through medication claims? - Page 9, Lines 8-13: Benzodiazepines appear to be grouped into both hypnotics and anxiolytics. It would be helpful to know if medications were counted in both groups or if individual medications were differentially selected for each group and how that was determined?

Results: - Page 14, Lines 21-24: As the authors mention, the rate of antidepressant use is surprisingly low where use can exceed 50% in other countries. How does this compare to general prescribing rates of antidepressants to older adults in the community (non- facility settings) in Japan?

Limitations:

- This study does not provide information on PRN medication use, http://bmjopen.bmj.com/ so overall prevalence of use may be underestimated in this regard. - The study does not include a measure of antiepileptic or mood stabilizing medications which are commonly used off-label for treatment of behavioral disturbances in dementia (e.g., gabapentin, valproic acid). Why were these medications excluded?

VERSION 1 – AUTHOR RESPONSE on September 30, 2021 by guest. Protected copyright.

Comments to the Author (Reviewer: 1):

It is of great interest to explore the prescribing practice of drugs with anticholinergic properties in elderly persons, considering the risks associated with exposure to high anticholinergic load, especially in persons presenting with dementia. It is also of interest to investigate this issue in different countries with different organizations of care for these persons. The present study as several strengths particularly regarding deprescribing of drugs with deleterious side effects in elderly persons after admission in the Roken services. Unfortunately, this interesting point is not sufficiently developed. The present study is hampered by several methodological drawbacks that should be further addressed by the authors.

Response: Thank you very much for your review and providing us with your valuable comments and suggestions. According to your comments, we have added data on discontinuation of drugs after

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from admission to a facility. We use ‘discontinuation’ for this article rather than ‘deprescribing’ because we did not have sufficient information on the processes and reasons for discontinuation.

In the highlights section: please give the spelled-out form of the acronym NH/LTCFs.

Response: Thank you. We have revised the relevant section.

Article Summary (Page 4)

“The generalizability of our findings may be limited to similar types of nursing homes or long-term care facilities only.”

The aims of the study are unclear and do not match with the analyses reported in the manuscript. The most interesting part of the study is related to change of prescription over the 1st two months after admission. This issue is not mentioned in the aim section.

Response: Thank you for your suggestion. We have included the evaluation of changes in prescription after admission in the objectives sub-section of the abstract, as follows:

Abstract (Page 2) http://bmjopen.bmj.com/

“Objectives: To evaluate the prescription and discontinuation of psychotropic drugs (PD) and drugs with anticholinergic properties (DAP) in residents with dementia admitted to Roken, a major type of long-term care facility in Japan.”

Introduction (Page 6) on September 30, 2021 by guest. Protected copyright.

“We also aimed to identify factors associated with prescription and discontinuation of PD and DAP among Roken residents.”

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from Response: Thank you for your comment. We have added a new ‘Setting’ sub-section at the start of the Methods section to provide more information on Roken for international readers.

Our responses to each question are as follows:

- Are they private or public structures ? Roken is one of three types of LTCFs in Japan covered by public long-term care (LTC) systems, and >90% of Roken are private sector-operated.

- Which proportion of elderly persons are managed in these structures in Japan ? According to a national survey conducted in 2015, namely, the ‘Survey of Institutions and Establishments for Long-term Care’, the total capacity of Roken facilities was 368,201 residents nationwide. This figure corresponded to approximately 1% of older people aged ≥65 years or 8% of older people with long-term care needs.

- What is the mean age at admission ? We have added mean age (86 years; standard deviation, 7 years) to Table 1 and to online Supplemental Table S3.

- What is the organization of medical care i.e. who are the practitioners in charge of medication prescribing ? In general, a full-time medical director in a facility is in charge of and responsible for medication, and pharmacists, nurses, and other health staff contribute information to support decisions concerning residents’ medication.

- Are the drugs free of charge the patients ? Fees for medical, including pharmacotherapy and rehabilitation, and LTC services provided in

Roken are paid to the facility as a bundled payment from public LTC insurance systems. The fees http://bmjopen.bmj.com/ have been determined based on LTC needs for individual residents, the facility subtype of Roken, and on additional services, but not on drug costs. Out-of-pocket payment rates for Roken services generally comprise 10% of total expenditures. Therefore, in most cases, changes to medication do not affect residents’ out-of-pocket payments.

- It is also unclear for me whether the persons are living in the Roken as they are described as “resident” but it is also mentioned that the aim of the Roken is to improve functioning to live at home.

Are persons leaving the Roken once included, and if yes, what is the mean duration of stay ? on September 30, 2021 by guest. Protected copyright. We use the term “resident” in our study as well as other previous studies because most older adults are discharged from hospitals. Roken residents are stable in terms of medical conditions, but they require specific care and rehabilitation prior to returning home. The mean length of stay has been reported to be approximately 10 months.

Setting (Pages 6-7)

“Setting

Roken is one of three types of LTCFs in Japan covered by public LTC insurance systems, and >90% of Roken are private sector-operated.[27] According to a national survey conducted in 2015, namely, the ‘Survey of Institutions and Establishments for Long-term Care,’ the total capacity of Roken facilities was 368,201 residents nationwide.[28] This figure corresponded to approximately 1% of older people aged ≥65 years or 8% of older people with LTC needs. The majority of older adults are admitted to a facility after discharge from a hospital.[27] Roken residents are stable in terms of medical conditions, but they require specific care and rehabilitation prior to returning home. The mean

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from length of stay has been reported to be approximately 10 months.[27] General services in Roken comprise routine medical and LTC services, with some exceptions.

Fees for medical, including pharmacotherapy and rehabilitation, and LTC services provided in Roken are paid to the facility as a bundled payment from public LTC insurance systems. The fees have been determined based on LTC needs for individual residents, the facility subtype of Roken, and on additional services, but not on drug costs. Out-of-pocket payment rates for Roken services generally comprise 10% of total expenditures. Therefore, in most cases, changes to medication do not affect residents’ out-of-pocket payments.

In general, a full-time medical director in a facility is in charge of and responsible for medication, and pharmacists, nurses, and other staff contribute information to support decisions concerning residents’ medication. Information regarding medication prescribed at admission is generally obtained from a drug information sheet issued by a physician in charge of an individual prior to admission to a facility. Social workers and other facility staff may obtain additional information from staff members in a hospital prior to admission or from primary care professionals.”

The rationale and method used to identify the sample of Roken under study is unclear. Why only 368 Roken were included ? How many Roken were existing in Japan in 2005 (3,598? ) i.e. which proportion of the total number of Roken is included in the present study ?

Response: Thank you for your question. We administered a questionnaire survey via mail because this was our only option for collecting data in this way due to two main reasons. Medical claims data for drugs were not generally issued for Roken residents due to a bundled payment from public long- term care system, which is separately implemented from public medical insurance systems in Japan. Furthermore, most Roken had not introduced unified electronic systems to record drug prescriptions. http://bmjopen.bmj.com/

Therefore, we asked the facilities to collect five randomly selected residents, with consideration to time spent and efforts in collecting data, to mitigate sampling bias from a facility. However, the response rate for drug utilization survey was only approximately 10% (n = 368 of 3,598 facilities nationwide; more precisely, Roken, registered with the Japan Association of Geriatric Health Services

Facilities). We acknowledge that the low response rate of the survey limits the generalizability of the on September 30, 2021 by guest. Protected copyright. study findings and we have mentioned this in the Discussion section. However, we consider the data analyzed in this study are the best available data to evaluate medication use in Roken facilities nationwide.

Abstract (Page 2)

“Participants: This study included 1,201 residents from 343 Roken (response rate: 10%). We determined the presence and severity of dementia using a nationally standardized measure.”

Data source (Page 8)

“We sent questionnaires via mail to obtain data regarding drug utilization to 3,598 Roken in 2015. Details on the survey have been previously reported.[25] This data collection method was applied at that time because medical claims data for drugs were not generally issued for Roken residents and

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from most Roken facilities had not introduced standardized electronic systems to record drug prescriptions.”

Study participants (Page 9)

“The selection of study participants has been previously described.[25,26] From data collected using the survey on 1,510 residents at 368 Roken (response rate: 10.2%), we first selected residents aged ≥65 years who had stayed at the same facility for at least two consecutive months after admission.”

Response: Thank you for your comment. Information on drugs prescribed at admission are generally obtained from the drug information sheet that had been issued by a physician in charge of an individual prior to admission to a facility. Social workers and other staff in the facility may obtain additional information from the staff members at a hospital before the admission or from primary care professionals. For this study, we did not provide directions for the way in which to collect data on prescriptions; however, we expected respondents to follow the standard manner in which to report prescription data.

Setting (Page 7) http://bmjopen.bmj.com/ “Information regarding medication prescribed at admission is generally obtained from a drug information sheet issued by a physician in charge of an individual prior to admission to a facility. Social workers and other facility staff may obtain additional information from staff members in a hospital prior to admission or from primary care professionals.”

Which classification was used to categorize the psychotropic drugs ? The list provided is not on September 30, 2021 by guest. Protected copyright. sufficient, the categories have to be defined according to international classifications (ATC for instance). It is really difficult to understand why mood stabilizers were not included in a study on psychotropic drugs. This issue is problematic considering the case definition of dementia, as persons presenting with severe mental illness such as bipolar disorder or schizophrenia may be diagnosed as presenting with dementia, and these persons are frequently treated by mood stabilizers (lithium or anticonvulsants).

Response: Thank you for your comment. We have included a complete list of the psychotropic drugs we studied in online Supplemental Table S1, which were at least once used in this study sample, along with ATC codes and drug names. At this revision, we have also included antiepileptic drugs and lithium.

Drugs of interest (Page 10)

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from “PD comprised the following six categories: antipsychotics (first- and second-generation), antidepressants, hypnotics, anxiolytics, antiepileptic drugs, and lithium (online Supplemental Table S1).”

Drug utilization (Page 13)

“At least one category of PD was prescribed to >40% of the residents. The most frequently prescribed drug category was hypnotics, followed by antipsychotics, anxiolytics, antidepressants, and antiepileptic drugs. Among residents with antiepileptic drugs, 23 (27.1%) residents at admission and 24 (25.5%) residents at two months after admission had a recorded diagnosis of symptomatic epilepsy. Lithium was rarely prescribed.”

Supplemental Table S1. Psychotropic drugs investigated in the study

ATC codes Drug names

Antipsychotics (N05A) [excluding lithium (N05AN)]

First-generation N05AA Chlorpromazine, Levomepromazine

N05AB Perphenazine

N05AD Haloperidol

N05AL Sulpiride, Tiapride

Not assigned Propericiazine http://bmjopen.bmj.com/

Second-generation N05AH Olanzapine, Quetiapine

N05AX Risperidone, Aripiprazole, Paliperidone

Not assigned Blonanserin, Perospirone

Antidepressants (N06A) on September 30, 2021 by guest. Protected copyright.

Non-selective monoamine N06AA Imipramine, Clomipramine, Lofepramine, reuptake inhibitors Amitriptyline, Maprotiline

Not assigned Setiptiline

Selective serotonin N06AB Paroxetine, Sertraline, Fluvoxamine, reuptake inhibitors Escitalopram

Others N06AX Mianserin, Trazodone, Mirtazapine, Milnacipran, Duloxetine

Hypnotics and sedatives (N05C)

Barbiturates N05CA Amobarbital

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from N05CB Phenobarbital + Chlorpromazine + Promethazine

Benzodiazepines N05CD Nitrazepam, Flunitrazepam, Estazolam, Triazolam, Lormetazepam, Brotizolam

Not assigned Rilmazafone

Benzodiazepine related N05CF Zopiclone, Zolpidem, Eszopiclone drugs (Z-drugs)

Others N05CH Ramelteon

N05CM Suvorexant

Anxiolytics (N05B)

Benzodiazepines N05BA Diazepam, Chlordiazepoxide, Medazepam, Potassium clorazepate, Lorazepam, Alprazolam, Fludiazepam, Ethyl loflazepate, Etizolam, Clotiazepam

Not assigned Oxazolam

Others Not assigned Tandospirone

Antiepileptics (N03A)

Antiepileptics N03AA Phenobarbital, Primidone

N03AB Phenytoin http://bmjopen.bmj.com/

N03AE Clonazepam

N03AF Carbamazepine

N03AG Valproic acid

N03AX Lamotrigine, Levetiracetam, Zonisamide on September 30, 2021 by guest. Protected copyright.

Lithium (N05AN)

Lithium N05AN Lithium

ATC, Anatomical Therapeutic Chemical Classification System

The drug names listed were prescribed at least once in the study cohort.

Prochlorperazine (N05AB), hydroxyzine (N05BB), and pregabalin (N03AX) were not included in this study because these drugs were predominantly used for other indications in Japan.

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from another ; sulpiride is not considered as a 2nd generation antipsychotics in the literature, amisulpride is the only benzamide drug categorized as 2nd generation.

Response: We are sorry that the description concerning the classification of sulpiride was misleading. We included sulpiride in first-generation (typical) antipsychotics in our original submission. We noted the inclusion of sulpiride in antipsychotics as sulpiride is also commonly used as a drug for gastrointestinal symptoms in Japan. However, we have now included a complete list of psychotropic drugs studied (please see online Supplemental Table S1), and we have now removed the description of sulpiride from the main body of the manuscript.

The definition of psychotropic polypharmacy is also problematic regarding the issue explored in the present study. Polypharmacy may also be related to the co-prescription of several drugs from the same pharmacological category for instance 2 antipsychotics or 2 antidepressants.

Response: Thank you for your indication. We have removed the descriptions and evaluation of psychotropic polypharmacy from the manuscript.

The method used to assess anticholinergic activity is questionable. It is true that various scales are available, but some of them are more reliable than others. It is acknowledged that the most relevant are those assessing an anticholinergic score : see for instance Salahudeen, M. S., Duffull, S. B. & Nishtala, P. S. (2015). Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review. BMC http://bmjopen.bmj.com/ Geriatrics 15, 31 ; Duran, C. E., Azermai, M. & Vander Stichele, R. H. (2013). Systematic review of anticholinergic risk scales in older adults. Eur J Clin Pharmacol 69, 1485-96. Hence, the findings of the present study regarding this variable should be considered with cautious.

Response: Thank you for your comment. As you have mentioned, the list in the new national on September 30, 2021 by guest. Protected copyright. guidance has not been validated although it was developed based on the national guidelines and validated anticholinergic burden scales (i.e., Anticholinergic Risk Scale (ARS) and Beers criteria). At this revision, for better screening of drugs with anticholinergic properties, we have also included drugs listed in the ARS and Beers criteria in addition to drugs listed in the national guidance.

Drugs of interest (Page 10)

“We identified 11 DAP categories for screening purposes according to drugs listed in the ‘Guidance of Appropriate Medication for Elderly Patients’ released in May 2018 in Japan,[35] the Anticholinergic Risk Scale,[36] and/or the Beers criteria,[37] and on availability in Japan (online Supplemental Table S2).”

Drug utilization (Page 15)

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from “More than one-third of study participants were prescribed DAP, and this proportion did not change from admission to two months after admission (for all participants, 35.2% to 36.6%, P = 0.165). H2- blockers were the most frequently prescribed DAP, and the prescription rate increased from admission to two months after admission in all participants (13.5% to 15.9%, P < 0.001). Famotidine accounted for 80% of H2-blockers at admission and two months after admission. Related to the increased use of H2-blockers, the prescription of proton pump inhibitors decreased from 32.2% (n = 387) at admission to 26.3% (n = 316) at two months after admission. Antipsychotics and muscarinic receptor antagonists for overactive bladder were also frequently prescribed DAP.”

Discussion (Pages 20-21)

“We conducted screening for DAP with reference to lists provided in Japan’s national guidelines document (‘Guidance of Appropriate Medication for Elderly Patients’), the Anticholinergic Risk Scale and Beers criteria, without quantification of anticholinergic burdens.”

Supplemental Table S2. Drugs with anticholinergic properties investigated in the study

Category Class & Drug substance Extended list

(National guidance) (National guidance, ARS, Beers criteria)

Antidepressants  Tricyclic antidepressants (all) + Mirtazapine e.g. Imipramine, Clomipramine, Amitriptyline + Trazodone  Paroxetine Antipsychotics  Phenothiazine antipsychotics (all) + Haloperidol http://bmjopen.bmj.com/ e.g. Chlorpromazine, Levomepromazine + Quetiapine  Olanzapine, Clozapine + Risperidone

Drugs for Parkinson’s  Trihexyphenidyl + Amantadine disease  Biperiden + Carbidopa-levodopa on September 30, 2021 by guest. Protected copyright. + Entacapone

+ Pramipexole

+ Selegiline

Antiarrhythmic drugs  Disopyramide –

Skeletal muscle  Tizanidine + Baclofen relaxants + Methocarbamol

+ Pancuronium

+ Thioridazine

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from Drugs for overactive  Muscarinic receptor antagonists (all) + Flavoxate bladder e.g. Oxybutynin, Propiverine, Solifenacin Antispasmodic drugs  Antispasmodic drugs (all) – e.g. Atropine, Scopolamine butylbromide Antiemetics  Prochlorperazine –  Metoclopramide Histamine H2-receptor  Histamine H2-receptor antagonists – antagonists (all) e.g. Cimetidine, Ranitidine Histamine H1-receptor  First-generation histamine H1- + Cetirizine antagonists receptor antagonists (all) e.g. Chlorpheniramine, + Loratadine Diphenhydramine Others – + Dimenhydrinate

+ Loperamide

+ Trospium

ARS, Anticholinergic Risk Scale

Response: We have removed some data and descriptions from the main body of the manuscript. http://bmjopen.bmj.com/ Corresponding data have been moved to the Supplemental Material (online Supplemental Table S4).

analyses to explore this issue. It is much more interesting to explore the factors associated on September 30, 2021 by guest. Protected copyright. with change in prescription (especially deprescribing of drugs with cognitive side effects) rather than with prescriptions at one point.

Response: Thank you for your comment. We have explored the factors associated with discontinuation using multivariable logistic regression. As a result, we have identified some factors associated with discontinuation, but we could not analyze data according to drug categories nor obtain precise estimates because the relatively small numbers of participants were discontinued.

Abstract (Page 2)

“Primary and secondary outcome measures: Prescriptions of PD and DAP at admission and two months after admission were evaluated. Multivariable logistic regression was used to evaluate the associations of residents’ baseline characteristics with prescriptions or discontinuation.”

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from

Abstract (Pages 2-3)

“At an individual level, a quarter of residents prescribed PD or DAP at admission had discontinued at least one PD or DAP, respectively, two months after admission. Antidementia drug use in severe dementia (adjusted odds ratio, 1.86; 95% confidence interval, 1.04–3.31) and PD use in older age (1.61; 1.00–2.60; in residents with disabling dementia) were associated with discontinuation.”

Statistical analysis (Page 11)

“We defined discontinuation as no prescription for antidementia drugs or individual categories of PD as well as a decrease in the number of PD or DAP at two months after admission among users of the corresponding drugs at admission. Multivariable logistic regression analysis was used to evaluate the associations between residents’ baseline characteristics and prescription or discontinuation of antidementia drugs, PD, and DAP, and relevant adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) were reported.”

Drug utilization (Pages 15-16)

“Regarding changes in the use of drugs at an individual level, more than one-third of residents who were prescribed antidementia drugs at admission and >20% of residents who were prescribed PD or DAP at admission were discontinued the corresponding drugs at two months after admission. Only seven residents started antidementia drugs after admission, but the number of residents who started antipsychotics (n = 35) or DAP (n = 94) was comparable to those who discontinued (n = 30 or 113, respectively). The number of residents who started hypnotics, anxiolytics, or antidepressants was about half the number of residents who discontinued.” http://bmjopen.bmj.com/

Factors associated with discontinuation (Page 16)

“Factors associated with discontinuation

Discontinuation of antidementia drugs was more likely in residents with severe dementia (aOR, 1.86; on September 30, 2021 by guest. Protected copyright. 95% CI, 1.04–3.31; P = 0.035) (Table 4). In residents with disabling dementia, those aged ≥85 years were more likely to have discontinued the use of PD (aOR, 1.61; 95% CI, 1.00–2.60; P = 0.049) (online Supplemental Table S6).”

Table 4. Association between residents’ characteristics at admission and discontinuation during the first two months after admission

Severe dementia Bedridden Age, ≥85 years Women Factors (ref. Mild-to- (ref. Not (ref. 65–84) (ref. Men) moderate) bedridden)

aOR P- aOR P- aOR P- aOR P- (95% value (95% CI) value (95% CI) value (95% CI) value CI)

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from Antidementi 0.91 0.95 1.86 1.03 0.75 0.88 0.03 0.91 a drugs (0.52– (0.47– (1.04– (0.59– 0 1 5 3 1.60) 1.90) 3.31) 1.81)

Psychotropi 1.42 0.97 0.73 1.24 0.11 0.89 0.15 0.36 c drugs† (0.92– (0.58– (0.47– (0.78– 3 0 1 3 2.20) 1.59) 1.12) 1.97)

Drugs with 0.91 0.85 0.85 1.56 anticholiner 0.73 0.56 0.52 0.14 (0.54– (0.48– (0.50– (0.86– gic 3 9 6 3 1.53) 1.50) 1.42) 2.85) properties† aOR, adjusted odds ratio; CI, confidence interval

†Discontinuation of psychotropic drugs (PD) or drugs with anticholinergic drugs (DAP) overall was defined as a decrease in the number of drug categories from PD or DAP, respectively, from admission to month 2.

Response: Thank you for your suggestions. We have added the numbers and frequencies of discontinuation at an individual level in Table 2. We have also conducted multivariable analyses to http://bmjopen.bmj.com/ evaluate associations between discontinuation and some patients’ characteristics. Please also refer to our responses in the above comments.

Table 2. Utilization of antidementia drugs, psychotropic drugs, and drugs with anticholinergic properties on September 30, 2021 by guest. Protected copyright.

Discontinuation Admission Month 2 P-value (n, % of users at (n, %) (n, %) admission)†

Antidementia drugs 233 (19.4) 156 (13.0) <0.001 84 (36.1)

Psychotropic drugs 532 (44.3) 514 (42.8) 0.089 113 (23.2)

Hypnotics 301 (25.1) 272 (22.6) 0.002 58 (19.3)

Antipsychotics 158 (13.2) 163 (13.6) 0.535 30 (19.0)

First-generation 68 (5.7) 70 (5.8) 0.715 14 (20.6)

Second-generation 101 (8.4) 105 (8.7) 0.564 22 (21.8)

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from Anxiolytics 148 (12.3) 128 (10.7) 0.003 33 (22.3) NA, not Antidepressants 89 (7.4) 81 (6.7) 0.134‡ 15 (16.9)

Antiepileptic drugs 85 (7.1) 94 (7.8) 0.029 4 (4.7)

Lithium 2 (0.2) 2 (0.2) NA 0 (0.0)

Drugs with 77 (26.1) anticholinergic 423 (35.2) 440 (36.6) 0.165 properties

Frequently prescribed

drugs§

H2-receptor 20 (12.3) 162 (13.5) 191 (15.9) <0.001 antagonists

Antipsychotics 106 (8.8) 113 (9.4) 0.336 23 (21.7)

Drugs for overactive 14 (19.2) 73 (6.1) 69 (5.7) 0.541‡ bladder

Drugs for Parkinson’s 7 (12.5) 56 (4.7) 54 (4.5) 0.774‡ disease

Antidepressants 55 (4.6) 55 (4.6) 1.000‡ 8 (14.5) available

†Discontinuation of psychotropic drugs (PD) or drugs with anticholinergic drugs (DAP) overall was

defined as a decrease in the number of drug categories from PD or DAP, from admission to month http://bmjopen.bmj.com/ 2, respectively.

‡Exact P-values are shown in cases where a small number of residents (less than 30 residents) changed the prescription.

§See online Supplemental Table S2 for specific drugs included in each drug category.

Response: Thank you for your suggestion. We have analyzed antipsychotics overall and according to generation.

Yokukansan, a traditional Japanese Kampo medicine, is presented in the result section, and should be presented first in the method section with further explanations on this treatment.

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from Response: Thank you for your comment. We have introduced this drug in the Methods section, and we have included a relevant reference.

Drugs of interest (Page 10)

“In addition, the use of yokukansan, a traditional Japanese Kampo medicine, was also studied although this drug was not included in the PD categories. A meta-analysis of randomized controlled trials showed that yokukansan had beneficial effects on some symptoms related to dementia, including delusions, hallucinations, and agitation/aggression.[33]”

Response: Thank you for your comment. We have added some descriptions on discontinuation of drugs in the Discussion section, as follows:

Discussion (Page 19)

“Despite our observations concerning the discontinuation of PD and DAP, some drugs, especially antipsychotics and DAP, were commonly initiated. Antidementia drugs for severe dementia and PD http://bmjopen.bmj.com/ for older aged residents (with disabling dementia) were identified as being associated with discontinuation. Larger studies are needed to evaluate discontinuation of individual drug categories in relation to PD or DAP.”

“Antidementia drugs were discontinued in about one-third of residents receiving these drugs at

admission, and residents with severe dementia were more likely to have had their antidementia drugs on September 30, 2021 by guest. Protected copyright. discontinued. This may be explained as due to the expected limited effectiveness of antidementia drugs, especially for those with severe dementia, or due to intolerability or issues concerning adverse effects.”

Discussion (Page 22)

“Similarly, we did not determine the processes or reasons for the discontinuation of drugs, and further studies are needed to evaluate the appropriateness of drug discontinuation.”

Comments to the Author (Reviewer: 2):

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from In this study the authors evaluated the prevalence of psychotropic and anticholinergic medication prescribing to residents in long-term care facilities (Roken) in Japan. Use of potentially inappropriate medications among nursing home residents and residents with dementia is a major issue given the risk of medication related harms. This study provides useful information regarding psychotropic and anticholinergic medication prevalence within Roken as well as factors associated with prescribing. The manuscript could be strengthened through the following revisions.

Response: Thank you for your review and valuable comments and suggestions. We believe the manuscript has been substantially improved.

Major Issues:

Introduction (Page 6, Lines 19-26):

The Introduction overall would be strengthened by providing a little more information regarding Roken for International readers to best place this type of care facility in context. From the description provided, Roken may sound more similar to a subacute rehabilitation facility in the U.S., rather than a long-term care nursing home where the majority of previous work regarding psychotropic prescribing has been performed.

Response: Thank you for your comment. We have included a new sub-heading: ‘Setting,’ at the beginning of the Methods section to provide more information on Roken facilities for international readers. http://bmjopen.bmj.com/

Methods:

Overall it would be helpful to provide more information about who are the respondents filling out the surveys and how they were selected. Are these families of patients with dementia, facility staff caring for the patient, or patients themselves in some cases? A description of how it was determined who would fill out the survey would be helpful as well as the on September 30, 2021 by guest. Protected copyright. breakdown of respondents for the information presented here (if available).

Response: Thank you for your comment. Although staff other than medical directors might fill out the surveys, medical directors in Roken facilities were responsible for responding to the survey. No residents or their families were involved in completing the surveys.

Data source (Page 8)

“Medical directors or facility managers in individual Roken facilities were responsible for responding to the survey. No residents or their families were involved in completing the survey.”

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from Discussion:

-It would be helpful to provide some information regarding potential regulatory pressures or initiatives to reduce antipsychotic prescribing in Japan. For instance, in the U.S. nursing home antipsychotic prescribing rates publicly reported and impact nursing facilities ratings through a Five Star Rating System. Is there similar public reporting or regulatory pressures/initiatives to drive down antipsychotic prescribing in Roken? This information would be helpful for readers to put in context the various factors that may be influencing prescribing.

Response: Thank you for your comment. We recognize some successful efforts to reduce antipsychotic use in nursing homes in the US and other countries. To date, there have not been no public reporting system or regulatory actions undertaken to reduce antipsychotic use in Japan.

Discussion (Page 20)

“Some successful measures to reduce antipsychotic prescriptions in NH have been reported in other countries, such as the United States and Canada;[42,43] however, similar regulatory initiatives have not yet been implemented in Japan.”

Minor Issues:

Methods:

- Were medications only captured by the results of the survey or also through medication claims? http://bmjopen.bmj.com/

Response: Thank you for your comment. Data on medications were obtained only from the survey. Medication claims are not issued for drugs prescribed in Roken because drug costs are bundled in payments from public long-term care insurance systems. This has made us difficult to understand medication use in Roken residents. In addition, the majority of the facilities did not introduce electronic

medical records to manage medical information. Therefore, our only option was to obtain data on on September 30, 2021 by guest. Protected copyright. medication use from the questionnaire survey via mail.

Data source (Page 8)

Methods:

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from - Page 9, Lines 8-13: Benzodiazepines appear to be grouped into both hypnotics and anxiolytics. It would be helpful to know if medications were counted in both groups or if individual medications were differentially selected for each group and how that was determined?

Response: Benzodiazepines were categorized into either hypnotics or anxiolytics according to the ATC classification system (please see new online Supplemental Table S1). In general, we separately evaluated hypnotics and anxiolytics.

In addition, we also calculated the prevalence of all hypnotic and anxiolytic benzodiazepines and Z- drugs together because we considered that it would be informative to compare our results with those of previous studies undertaken in Japan and in other countries that reported the prescription rate of all benzodiazepines. The results are shown in the main text in the ‘Drug utilization’ sub-section of the Results section.

Results:

- Page 14, Lines 21-24: As the authors mention, the rate of antidepressant use is surprisingly low where use can exceed 50% in other countries. How does this compare to general prescribing rates of antidepressants to older adults in the community (non-facility settings) in Japan?

Response: The prescription rate of antidepressants in the present study was considerably lower than http://bmjopen.bmj.com/ that reported in other countries. However, the prescription rate of antidepressants in our study was twice as high as that in older outpatients aged ≥75 years (3.7%). We have added this in the Discussion.

Discussion (Page 21) on September 30, 2021 by guest. Protected copyright. “The prevalence of antidepressants was twice as high as that in older outpatients aged ≥75 years (3.7%) in Japan.[45] However, the prescription rate in our study was considerably lower compared with that reported in studies conducted in other countries, with approximately one-fifth to two-thirds of NH residents with or without dementia reported to have received antidepressants.[11-17,20]”

Reference

Ishizaki T, Mitsutake S, Hamada S, Teramoto C, Shimizu S, Akishita M, Ito H. Drug prescription patterns and factors associated with polypharmacy in >1 million older adults in Tokyo. Geriatr Gerontol Int 2020;20:304–11.

Limitations:

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from - This study does not provide information on PRN medication use, so overall prevalence of use may be underestimated in this regard.

Response: Thank you for your comment. We could not evaluate as-needed drugs because of data collection reasons (1st paragraph of ‘Drugs of interest’ in the Methods). We have described the possibility of overestimation of medication use due to incomplete recording of ‘as-needed’ directions in the limitations of this study. However, as the reviewer had indicated, we totally agree that we should include the possibility of underestimation of medication use as a limitation because we did not include PRN drugs.

Discussion (Page 23)

“We considered that these limitations may cause overestimation of the prevalence of drugs because of drugs without directions possibly being included as regularly scheduled drugs, or underestimation in cases involving as-needed drugs, which may have been important components of usual medications. As-needed drugs should also be considered as part of complex drug regimens for NH/LTCF residents in future studies.[52]”

Limitations:

- The study does not include a measure of antiepileptic or mood stabilizing medications which are commonly used off-label for treatment of behavioral disturbances in dementia (e.g., gabapentin, valproic acid). Why were these medications excluded?

http://bmjopen.bmj.com/

Response: Thank you for your comment. We have evaluated the use of antiepileptic drugs and lithium, as possible mood stabilizers (please see online Supplemental Table S1). We have also examined the presence of a recorded diagnosis of symptomatic epilepsy in users of antiepileptic drugs.

“Results: Prescription rates decreased for antidementia drugs (19.4% to 13.0%), hypnotics (25.1% to 22.6%), and anxiolytics (12.3% to 10.7%), whereas those for other PD, such as antipsychotics (13.2% to 13.6%), antidepressants (7.4% to 6.7%), antiepileptic drugs (7.1% to 7.8%), and DAP (35.2% to 36.6%) did not statistically significantly decrease.”

Drugs of interest (Page 10)

“PD comprised the following six categories: antipsychotics (first- and second-generation), antidepressants, hypnotics, anxiolytics, antiepileptic drugs, and lithium (online Supplemental Table S1).”

Drug utilization (Page 13)

BMJ Open: first published as 10.1136/bmjopen-2020-045787 on 8 April 2021. Downloaded from “At least one category of PD was prescribed to >40% of the residents. The most frequently prescribed drug category was hypnotics, followed by antipsychotics, anxiolytics, antidepressants, and antiepileptic drugs. Among residents with antiepileptic drugs, 23 (27.1%) residents at admission and 24 (25.5%) residents at two months after admission had a recorded diagnosis of symptomatic epilepsy. Lithium was rarely prescribed.”

VERSION 2 – REVIEW

REVIEWER Gerlach, Lauren B University of Michigan REVIEW RETURNED 08-Mar-2021

GENERAL COMMENTS The authors have addressed all previous concerns and suggestions.