1 Supplemental Material Supplemental Table S1

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Supplemental Material

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 Second-generation N05AH Olanzapine, Quetiapine N05AX Risperidone, Aripiprazole, Paliperidone Not assigned Blonanserin, Perospirone Antidepressants (N06A) Non-selective monoamine N06AA Imipramine, Clomipramine, Lofepramine, Amitriptyline, reuptake inhibitors Maprotiline Not assigned Setiptiline Selective serotonin reuptake N06AB Paroxetine, Sertraline, Fluvoxamine, Escitalopram inhibitors Others N06AX Mianserin, Trazodone, Mirtazapine, Milnacipran, Duloxetine Hypnotics and sedatives (N05C) Barbiturates N05CA Amobarbital 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 N03AE Clonazepam N03AF Carbamazepine N03AG Valproic acid N03AX Lamotrigine, Levetiracetam, Zonisamide 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.

Hamada S, et al. BMJ Open 2021; 11:e045787. doi: 10.1136/bmjopen-2020-045787 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Open

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, + Trazodone Amitriptyline  Paroxetine Antipsychotics  Phenothiazine antipsychotics (all) + Haloperidol e.g. Chlorpromazine, Levomepromazine + Quetiapine  Olanzapine, Clozapine + Risperidone Drugs for Parkinson’s  Trihexyphenidyl + Amantadine disease  Biperiden + Carbidopa-levodopa + Entacapone + Pramipexole + Selegiline Antiarrhythmic drugs  Disopyramide – Skeletal muscle  Tizanidine + Baclofen relaxants + Methocarbamol + Pancuronium + Thioridazine 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 (all) – antagonists e.g. Cimetidine, Ranitidine Histamine H1-receptor  First-generation histamine H1-receptor + Cetirizine antagonists antagonists (all) + Loratadine e.g. Chlorpheniramine, Diphenhydramine Others – + Dimenhydrinate + Loperamide + Trospium ARS, Anticholinergic Risk Scale

Supplemental Table S3. Characteristics of residents with disabling dementia at admission according to dementia severity Dementia severity Overall Moderate Severe P value (n = 1,057) (n = 498) (n = 559) Age (years) 65–74 79 (7.5) 36 (7.2) 43 (7.7) 0.773 75–84 329 (31.1) 157 (31.5) 172 (30.8) 85–94 544 (51.5) 251 (50.4) 293 (52.4) 95+ 105 (9.9) 54 (10.8) 51 (9.1) Mean ± SD 86 ± 7 86 ± 7 86 ± 7 0.847 Sex Men 262 (24.8) 114 (22.9) 148 (26.5) 0.178 Women 795 (75.2) 384 (77.1) 411 (73.5) Physical disability Non-bedridden 336 (31.8) 212 (42.6) 124 (22.2) <0.001 Bedridden 721 (68.2) 286 (57.4) 435 (77.8) SD, standard deviation

Supplemental Table S4. Utilisation of antidementia drugs, psychotropic drugs and drugs with anticholinergic properties according to dementia severity Dementia severity Mild-to-moderate Moderate-to-severe Moderate Severe Discontinu Discontinu Discontinu Discontinu Admission Month 2 -ation Admission Month 2 -ation Admission Month 2 -ation Admission Month 2 -ation n (% of n (% of n (% of n (% of n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) users at users at users at users at admission)† admission)† admission)† admission)† Antidementia drugs 100 (15.6) 76 (11.8) 28 (28.0) 223 (21.1) 149 (14.1) 80 (35.9) 90 (18.1) 69 (13.9) 24 (26.7) 133 (23.8) 80 (14.3) 56 (42.1) Psychotropic drugs 281 (43.8) 255 (39.7) 65 (23.1) 465 (44.0) 456 (43.1) 96 (20.6) 214 (43.0) 197 (39.6) 48 (22.4) 251 (44.9) 259 (46.3) 48 (19.1) Hypnotics 172 (26.8) 150 (23.4) 31 (18.0) 254 (24.0) 236 (22.3) 47 (18.5) 125 (25.1) 114 (22.9) 20 (16.0) 129 (23.1) 121 (21.6) 27 (20.9) Antipsychotics 57 (8.9) 53 (8.3) 11 (19.3) 148 (14.0) 154 (14.6) 28 (18.9) 47 (9.4) 44 (8.8) 9 (19.1) 101 (18.1) 112 (20.0) 19 (18.8) Anxiolytics 93 (14.5) 78 (12.1) 20 (21.5) 125 (11.8) 108 (10.2) 30 (24.0) 70 (14.1) 58 (11.6) 17 (24.3) 55 (9.8) 50 (8.9) 13 (23.6) Antidepressants 49 (7.6) 43 (6.7) 9 (18.4) 79 (7.5) 71 (6.7) 13 (16.5) 39 (7.8) 33 (6.6) 7 (17.9) 40 (7.2) 38 (6.8) 6 (15.0) Antiepileptic drugs 40 (6.2) 40 (6.2) 2 (5.0) 75 (7.1) 84 (7.9) 3 (4.0) 30 (6.0) 30 (6.0) 1 (3.3) 45 (8.1) 54 (9.7) 2 (4.4) Lithium 2 (0.3) 2 (0.3) 0 (0.0) 1 (0.1) 1 (0.1) 0 (0.0) 1 (0.2) 1 (0.2) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Drugs with anticholinergic 204 (31.8) 217 (33.8) 38 (18.6) 378 (35.8) 395 (37.4) 68 (18.0) 159 (31.9) 172 (34.5) 29 (18.2) 219 (39.2) 223 (39.9) 39 (17.8) properties Frequently prescribed drugs‡ H2-receptor antagonists 88 (13.7) 105 (16.4) 11 (12.5) 146 (13.8) 171 (16.2) 19 (13.0) 72 (14.5) 85 (17.1) 10 (13.9) 74 (13.2) 86 (15.4) 9 (12.2) Antipsychotics 38 (5.9) 36 (5.6) 8 (21.1) 99 (9.4) 106 (10.0) 22 (22.2) 31 (6.2) 29 (5.8) 7 (22.6) 68 (12.2) 77 (13.8) 15 (22.1) Drugs for overactive bladder 37 (5.8) 39 (6.1) 5 (13.5) 61 (5.8) 60 (5.7) 11 (18.0) 25 (5.0) 30 (6.0) 2 (8.0) 36 (6.4) 30 (5.4) 9 (25.0) Drugs for Parkinson’s 24 (3.7) 25 (3.9) 3 (12.5) 48 (4.5) 47 (4.4) 6 (12.5) 16 (3.2) 18 (3.6) 2 (12.5) 32 (5.7) 29 (5.2) 4 (12.5) disease Antidepressants 23 (3.6) 23 (3.6) 4 (17.4) 48 (4.5) 46 (4.4) 7 (14.6) 16 (3.2) 14 (2.8) 3 (18.8) 32 (5.7) 32 (5.7) 4 (12.5) †Discontinuation of psychotropic drugs (PD) or drugs with anticholinergic properties (DAP) overall was defined as a decrease in the number of drug categories from PD or DAP, from admission to month 2, respectively. ‡See online supplemental table S2 for specific drugs included in each drug category.

Supplemental Table S5. Associations of residents’ characteristics at admission with the prescriptions 2 months after admission in residents with disabling dementia Age, ≥85 years Women Severe dementia Bedridden Factors (ref. 65–84) (ref. men) (ref. moderate) (ref. not bedridden) aOR (95% CI) P value aOR (95% CI) P value aOR (95% CI) P value aOR (95% CI) P value Antidementia drugs 0.90 (0.62 to 1.30) 0.567 1.56 (0.99 to 2.47) 0.054 1.28 (0.89 to 1.84) 0.183 0.42 (0.29 to 0.60) <0.001 Antipsychotics 0.63 (0.44 to 0.90) 0.012 1.31 (0.86 to 2.00) 0.212 3.09 (2.09 to 4.57) <0.001 0.61 (0.42 to 0.89) 0.010 First-generation 0.58 (0.34 to 0.96) 0.035 1.31 (0.71 to 2.42) 0.383 2.56 (1.46 to 4.49) 0.001 0.66 (0.38 to 1.13) 0.126 Second-generation 0.65 (0.42 to 0.99) 0.047 1.26 (0.76 to 2.09) 0.369 2.79 (1.75 to 4.46) <0.001 0.62 (0.39 to 0.96) 0.034 Hypnotics 0.74 (0.54 to 0.99) 0.046 0.83 (0.60 to 1.17) 0.288 0.96 (0.71 to 1.29) 0.778 0.80 (0.58 to 1.09) 0.153 Anxiolytics 0.59 (0.39 to 0.89) 0.011 1.33 (0.81 to 2.17) 0.260 0.75 (0.50 to 1.12) 0.162 1.04 (0.67 to 1.61) 0.870 Antidepressants 0.48 (0.29 to 0.78) 0.003 1.15 (0.65 to 2.03) 0.633 1.09 (0.66 to 1.79) 0.738 0.77 (0.46 to 1.29) 0.325 Antiepileptic drugs 0.23 (0.14 to 0.38) <0.001 0.82 (0.50 to 1.34) 0.424 1.60 (0.99 to 2.59) 0.055 1.47 (0.85 to 2.54) 0.167 Drugs with anticholinergic properties 0.68 (0.52 to 0.88) 0.003 0.95 (0.71 to 1.28) 0.756 1.27 (0.98 to 1.64) 0.070 0.96 (0.73 to 1.27) 0.796 Factors associated with prescribing of lithium could not be evaluated because of the small number of participants who had been prescribed this drug. aOR, adjusted odds ratio; CI, confidence interval

Supplemental Table S6. Associations of residents’ characteristics at admission with discontinuation during the first 2 months after admission in residents with disabling dementia Age, ≥85 years Women Severe dementia Bedridden Factors (ref. 65–84) (ref. men) (ref. moderate) (ref. not bedridden) aOR (95% CI) P value aOR (95% CI) P value aOR (95% CI) P value aOR (95% CI) P value Antidementia drugs 0.84 (0.47 to 1.50) 0.559 1.03 (0.51 to 2.10) 0.935 1.95 (1.07 to 3.56) 0.029 1.16 (0.65 to 2.07) 0.610 Psychotropic drugs† 1.61 (1.00 to 2.60) 0.049 1.00 (0.58 to 1.73) 0.999 0.74 (0.46 to 1.19) 0.211 1.35 (0.81 to 2.25) 0.255 Drugs with anticholinergic 0.93 (0.54 to 1.61) 0.788 0.87 (0.48 to 1.57) 0.642 0.88 (0.50 to 1.55) 0.669 1.38 (0.73 to 2.61) 0.315 properties† aOR, adjusted odds ratio; CI, confidence interval †Discontinuation of psychotropic drugs (PD) or drugs with anticholinergic properties (DAP) overall was defined as a decrease in the number of drug categories from PD or DAP, respectively, from admission to month 2.

Hamada S, et al. BMJ Open 2021; 11:e045787. doi: 10.1136/bmjopen-2020-045787