Journal of Alzheimer’s Disease xx (2021) x–xx 1

DOI 10.3233/JAD-210142
IOS Press

1 Adjunctive Therapy to Manage

2 Neuropsychiatric Symptoms in Moderate
and Severe Dementia: Randomized Clinical

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3

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4 Trial Using an Outpatient Version of
5 Tailored Activity Program

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6 Alexandra Martini Oliveiraa,b,∗ , Marcia Radanovicb , Patricia Cotting Homem de Melloa ,
7 Patricia Cardoso Buchaina , Adriana Dias Barbosa Vizzottoa , Janaı́na Harderc , Florindo Stellab ,

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8 Laura N. Gitlind,e,f , Catherine Verrier Piersolg ,
9 Leandro L.C. Valiengob and Orestes Vicente Forlenzab
10
a Serviço de Terapia Ocupacional, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo,
11 Brazil
b Laboratorio de Neurociencias (LIM-27), Hospital das Clinicas, Faculdade de Medicina,
12
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13 Universidade de Sao Paulo, Brazil
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c Instituto de Psiquiatria, Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, Brazil

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d Johns Hopkins University School of Nursing, Baltimore, MD, USA

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e Johns Hopkins Center for Innovative Care in Aging, Baltimore, MD, USA

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f Drexel College of Nursing and Health Professions, Philadelphia, PA, USA
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g Department of Occupational Therapy, Thomas Jefferson University, Philadelphia, PA, USA

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20
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19 Accepted 19 June 2021

Pre-press 26 July 2021

21 Abstract.
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22 Background: Neuropsychiatric symptoms (NPS) such as aggression, apathy, agitation, and wandering may occur in up to
23 90% of dementia cases. International guidelines have suggested that non-pharmacological interventions are as effective as
24 pharmacological treatments, however without the side effects and risks of medications. An occupational therapy method,
25 called Tailored Activity Program (TAP), was developed with the objective to treat NPS in the elderly with dementia and has
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26 been shown to be effective.

27 Objective: Evaluate the efficacy of the TAP method (outpatient version) in the treatment of NPS in individuals with dementia
28 and in the burden reduction of their caregivers.
29 Methods: This is a randomized, double-blind, controlled clinical trial for the treatment of NPS in dementia. Outcome
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30 measures consisted of assessing the NPS of individuals with dementia, through the Neuropsychiatric Inventory-Clinician
31 rating scale (NPI-C), and assessing the burden on their caregivers, using the Zarit Scale. All the participants were evaluated
32 pre-and post-intervention.

∗ Correspondence to: Alexandra Martini de Oliveira, Ovidio Sao Paulo State 05403-010, Brazil. Tel.: +55 11 26618043; E-mail:
Pires de Campos Street, Number 785, Cerqueira Cesar, Sao Paulo, to.alexandramartini@gmail.com.

ISSN 1387-2877/$35.00 © 2020 – IOS Press and the authors. All rights reserved
 2 A.M. Oliveira et al. / Randomized Clinical Trial Using an Outpatient Version of Tailored Activity Program

33 Results: 54 individuals with dementia and caregivers were allocated to the experimental (n = 28) and control (n = 26) groups.
34 There was improvement of the following NPS in the experimental group: delusions, agitation, aggressiveness, depression,
35 anxiety, euphoria, apathy, disinhibition, irritability, motor disturbance, and aberrant vocalization. No improvement was
36 observed in hallucinations, sleep disturbances, and appetite disorders. The TAP method for outpatient settings was also
37 clinically effective in reducing burden between caregivers of the experimental group.
38 Conclusion: The use of personalized prescribed activities, coupled with the caregiver training, may be a clinically effective
39 approach to reduce NPS and caregiver burden of individuals with dementia.

Keywords: Caregiver burden, dementia, family caregiving, neuropsychiatric behaviors, non-pharmacologic intervention,

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41 occupational therapy

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33 INTRODUCTION drug-drug interactions that can give rise to these 73

symptoms [19]. 74

34 Neuropsychiatric symptoms (NPS) occur in up to The presence of NPS can lead to worse patient out- 75

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35 90% of patients with dementia over the course of the comes, accelerated disease progression (especially 76

36 disease [1–3]. NPS encompass a wide range of symp- depressive and psychotic symptoms), earlier insti- 77

37 toms that tend to aggregate in clusters identified as tutionalization, increased morbidity and mortality, 78

38 psychosis (delusions and hallucinations), agitation, increased caregivers’ burden, and higher treatment 79

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39 aggression, depression, anxiety, apathy, disinhibi- costs [20–23]. In the clinical practice, antipsychotics, 80

40 tion (socially and sexually inappropriate behaviors), benzodiazepines, or other sedative drugs are used 81

41 motor disturbance, night-time behaviors, and appetite despite the fact that these drugs are associated with 82

42 and eating problems [4], although there is recent a high risk of occurrence of adverse effects and 83

43 research suggesting that behaviors may cluster dif- increased mortality [7, 14, 24]. 84
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44 ferently depending on subtype or stage of dementia International guidelines have suggested that non- 85

45 [5]. The occurrence of NPS has been documented pharmacological interventions should be used prior 86

46 in most types of dementia such as Alzheimer’s dis- or as a complementary strategy to pharmacological 87

47 ease (AD), vascular dementia, dementia in Parkin- treatments because the latter have shown only modest 88

48 son’s disease, and frontotemporal dementia [6, 7]. benefit along with an increased risk for adverse out- 89

Population-based studies report that the frequency comes and do not address the behavioral symptoms
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49 90

50 of NPS, such as mild cognitive impairment (MCI), most upsetting to individuals living with dementia 91
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51 is much higher in people with AD even at early or their caregivers [12, 25–27]. The evidence of effi- 92

52 and prodromal stages when compared with the gen- cacy for non-pharmacological interventions has been 93

53 eral population [2, 8]. Types of behaviors and their accumulating over the last 15 years and these stud- 94

54 frequencies may also vary depending on stage of ies have shown to be effective in reducing functional 95

55 dementia. For example, in AD, depression, disinhibi- decline, decreasing service utilization [28], and NPS 96
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56 tion, apathy, and sleep disorders are prevalent in the [29]. Non-pharmacological interventions are primar- 97

57 initial stage, whereas the disease progression leads to ily designed to improve quality of life for people 98

58 an increase in delusions, hallucinations, and aggres- with dementia and their caregivers [28, 30]. The 99

59 sion [2, 9–11]. These behaviors are common and International Psychogeriatric Association [12] pub- 100
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60 often occurring simultaneously [12, 13]. lished a guideline suggesting that, prior to the use of 101

61 According to the literature, the causes of NPS an antipsychotic medication, patients with dementia 102

62 include neurobiologically related disease factors, should be assessed for the type, frequency, severity, 103

63 unmet needs, environmental triggers, and interac- clinical pattern, and timing of the NPS, including 104
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64 tions of the individual, caregiver, and environmental assessing for pain or other modifiable factors that may 105

65 factors [14]. Undiagnosed medical conditions are influence the choice of treatment. Also suggested was 106

66 also important contributors [15–17]. Hodgson et al. that treatment plans be individualized to reflect the 107

67 (2011) showed that 36% of older adults with demen- specific etiology and factors contributing to the NPS. 108

68 tia had an undetected illness that was associated with There are several non-pharmacological interven- 109

69 behavioral and psychological symptoms, including tions that may be effective for NPS, but the number 110

70 agitation, repeated questioning, crying out, delu- of clinical trials is limited [31]. Interventions tested 111

71 sions, and hallucinations [18]. Another possible cause using clinical trial methodology include caregiver 112

72 of NPS is related to the side effects of drugs or training in NPS management strategies, recreational 113
 A.M. Oliveira et al. / Randomized Clinical Trial Using an Outpatient Version of Tailored Activity Program 3

114 music therapy, aromatherapy, art therapy, behavioral MATERIALS AND METHODS 165

115 therapy, reality orientation, tailored activities, and

116 physical exercises [27, 31]. One of the most promis- Study design 166

117 ing approaches is the Tailored Activity Program

118 (TAP), which has been tested in various trials and A double-blind, randomized, controlled trial 167

119 in different countries. TAP is an occupational ther- (RCT) was conducted with 54 people living with 168

120 apy method which represents a palliative paradigm moderate to severe dementia and their primary fam- 169

121 different from curative methods commonly used in ily caregivers. As described elsewhere, TAP manuals 170

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122 rehabilitation settings. The TAP premise is that an and associated materials were translated into Brazil- 171

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123 activity can be designed for a person at any level ian Portuguese and adapted to an outpatient setting 172

124 of impairment as long as they are responsive to [35]. Participants were randomly assigned to one of 173

125 their environment. In the TAP, activities are prescri- two groups: an Experimental Group (EG), which 174

126 bed to capitalize on the preserved capabilities, str- received TAP, and a Control Group (CG), which 175

127 engths, and lifelong roles/interests, different from received psychoeducation. In both groups, each ses- 176

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128 intervention methods which emphasize new learning sion had a pre-fixed schedule of up to 1.5 h, for a 177

129 or seek to improve memory (a common goal imposed total of eight sessions over three months. All sessions 178

130 by cognitive rehabilitation context). Individuals with were performed at an outpatient clinic located in a ter- 179

131 moderate dementia who present cognitive impair- tiary university hospital. This trial was approved by 180

the institutional Ethics Committee and registered in

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132 ment but do not have the benefit of cognitive training, 181

133 may, however, benefit from procedural activities or the Brazilian Clinical Trials Registry (ReBec number 182

134 activities using repetitive actions such as washing RBR-66DH44). 183

135 dishes, sorting beads or cards; whereas individuals

136 with mild dementia may benefit from goal-directed
Setting and eligibility criteria
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137 activities such as arts and crafts, preparing simple
138 meals, painting, or puzzles. The purpose of the activ-
Participants were eligible for inclusion if they had: 185
139 ity is to engage the person and provide a pleasant
1) a diagnosis of dementia performed by a phy- 186
140 experience to promote a sense of self, connectedness,
sician; 2) with moderate to severe dementia con- 187
141 belonging, and identity with disease progression [21,
firmed by Mini-Mental State Examination (MMSE) 188
32–35].
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142
scores < 20; 3) presence of a caregiver for at least 189
143 Evidence suggests that Individuals living with
four hours per day; 4) the presence of at least 190
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144 dementia can effectively engage in activities graded

three types of NPS, identified by a questionnaire 191
145 to their abilities resulting in reduced NPS [32, 36, 37].
based on Neuropsychiatric Inventory Questionna- 192
146 The efficacy of TAP has been demonstrated in various
ire [33] just to identify the presence of these symp- 193
147 clinical trials including one study in Brazil [34]. In
toms at time of first contact; and 5) if taking 194
148 this Brazilian study of TAP home-based intervention,
psychotropic medications (antidepressants, benzod-
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195
149 Novelli et al. [34] demonstrated that after 4 months
iazepines, antipsychotics, or anticonvulsants) or an- 196
150 of implementation, individuals with dementia had a
tidementia medication (memantine or cholinesterase 197
151 reduced frequency and intensity of behaviors; care-
inhibitors), on a stable dose for 60 days prior 198
152 givers showed reduced distress and improved quality
to enrollment to minimize confounding effects of 199
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153 of life.
medications on NPS. Exclusion criteria were diag- 200
154 Although in Brazil, there is home care service in
nosis of schizophrenia, bipolar disorder, or dementia 201
155 the public health system which promotes palliative
secondary to head trauma, and being bed-bound (con- 202
156 and personalized care, there are some limitations and
fined to bed or chair) or nonresponsive (unable to
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203
157 difficulties, especially in large cities, related to time
understand short commands). 204
158 management for home visits since moving care to the
159 home generating a loss of time that is not always pre-
160 dictable [38]. Considering these contextual aspects, Recruitment 205

161 the present study aimed to investigate the effective-

162 ness of the TAP intervention adapted for an outpatient Participants were recruited between August 2015 206

163 clinic (Tailored Activity Program–outpatient version and May 2018 from different outpatient services 207

164 [TAP-O]) on reducing NPS in patients with moderate- through media, radio and television announcements. 208

severe dementia and caregiver burden. Interested caregivers contacted the research office 209
 4 A.M. Oliveira et al. / Randomized Clinical Trial Using an Outpatient Version of Tailored Activity Program

210 where they were explained the study’s procedures outpatient clinic, different from the TAP in-home 254

211 and the first screening appointment was scheduled. version where sessions occur at home. The book 255

included in the TAP-O was the same book used in 256

212 Randomization the TAP-Brazilian in-home version: You’re not Alone 257

[34]. Similar to the TAP in-home version, the TAP-O 258

213 Patients and their caregivers (dyads) were ran- is delivered by an occupational therapist and consists 259

214 domized using computer-generated block random- of eight face-to-face contacts that average 1 h each. 260

215 ization in blocks of six (available at http://www. TAP-O, as in the original, involves three phases: 261

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216 randomization.com). Randomization and allocation 1) the assessment of patients to identify cognitive 262

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217 concealment were centralized and the responsibility and functional capabilities (attention, ability to follow 263

218 of a single member of the research team who had no instructions, problem solving, and ability to learn) 264

219 contact with participants or researchers. and to characterize their previous abilities, interests, 265

and roles. In addition, caregivers learn about demen- 266

220 Sample size tia symptoms, how to manage NPS, and about stress 267

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reduction techniques; 2) the implementation of three 268

221 The sample size was calculated based on the activities, including the provision of strategies to sim- 269

222 clinical trial conducted by Giltin et al. [32] which plify communication and adapt activities based on the 270

223 compared an experimental group (TAP method) patient’s cognitive and functional profile to facilitate 271

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224 and a wait list control group. Based on previous engagement [39]. Caregivers are instructed on how to 272

225 studies of TAP and other similar studies testing non- implement these activities at home; 3) generalization 273

226 pharmacological studies, we determined that a total of techniques (e.g., cueing and other communica- 274

227 sample size between 50–60 (with wide range of stan- tion strategies) for daily activities, such as self care, 275

228 dard deviations of the primary outcome - reducing and methods for simplifying activities as the disease 276
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229 NPS) would have 80%–90% power to reject the null progresses [29, 32, 35]. 277

230 hypothesis that would be without difference between

231 groups. Control group: psychoeducation sessions 278

Participants in the control group received regu- 279

232 Blinding lar care and participated in psychoeducation group 280

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sessions, which were led by trained occupational ther- 281

233 Interviewers remained masked to group allocation apists over eight sessions in the outpatient clinic. 282
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234 throughout the study and participants were informed Similarly, to the TAP-O group, in the first session, 283

235 that they would be assigned to one of two types of printed material was provided to the caregiver with 284

236 caregiver training approaches [35]. information about dementia, activities, and commu- 285

nication. The content of subsequent sessions was 286

237 Intervention based on caregiver concerns and included education 287

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and the sharing of personal experiences. 288

238 Experimental group: TAP-O

239 The TAP-O (outpatient version) was adapted from Measurements 289

240 the TAP in-home version with the authorization of

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241 Laura N. Gitlin, PhD. Few modifications to the All dyads were evaluated at baseline or pre-inte- 290

242 protocol were required for implementation in an out- rvention (T0) and three months later, post-interven- 291

243 patient setting. The intervention protocol and written tion (T1). Outcome measures included behavioral 292

244 materials were translated from English to Brazilian symptoms using the Neuropsychiatric Inventory – 293
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245 Portuguese, then translated back into English. This Clinician Rating Scale (NPI-C) and caregiver burden 294

246 version was submitted for analysis by an experi- using the Zarit Scale. 295

247 enced occupational therapist from the original TAP The Brazilian version of the NPI-C [40, 41] 296

248 developer team. Finally, we retranslated TAP-O into is a comprehensive tool, which provides an accu- 297

249 Brazilian Portuguese. There were two modifications rate measurement of NPS with high concurrent 298

250 made to the original TAP: the context in which the validity and inter-rater reliability in the Brazilian 299

251 intervention was delivered and the resource book pro- setting [41]. The NPI-C consists of 14 psy- 300

252 vided to caregivers. Concerning the context, TAP chopathological domains: delusions, hallucinations, 301

253 outpatient version occurred at the hospital in an agitation, aggression, depression/dysphoria, anxiety, 302
 A.M. Oliveira et al. / Randomized Clinical Trial Using an Outpatient Version of Tailored Activity Program 5

303 elation/euphoria, apathy/indifference, disinhibition, Data analysis 324

304 irritability/lability, aberrant motor behavior, sleep

305 disorders, appetite and eating disorders, and aberrant Means and Median comparison between contin- 325

306 vocalizations. In the NPI-C, the clinician examines uous variables with free distribution was performed 326

307 the patient in addition to interviewing the caregiver using the Mann-Whitney test. For continuous vari- 327

308 and makes clinical judgments about the NPS [1]. ables with normal distribution, we used the Student’s 328

309 The score for each domain is the sum of clinical t-test for independent samples. For the comparison 329

310 impression ratings for all items, including informa- of categorical variables, the chi-squared test (χ2 ) 330

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311 tion about severity, frequency, and caregiver distress. and Fisher’s exact test were used, when appropriate. 331

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312 The clinician rating is a severity rating based on Results were considered significant at a p < 0.05. 332

313 all available clinical (e.g., medical records, personal Changes in the scores of NPS between pre- 333

314 observations, personal experience, and training) and (T0) and post-intervention (T1) were defined as the 334

315 interview information. primary outcome and changes in the intensity of care- 335

316 The Zarit burden Interview [42] is adapted for giver burden between pre- (T0) and post-intervention 336

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317 use in Brazil [43] and consists of 22 questions. The (T1) were defined as a secondary outcome. To assess 337

318 answer alternatives for each item are: never (0 points), the difference in the outcome of the two groups (EG 338

319 rarely (1 point), sometimes (2 points), very often (3 and CG) from T0 to T1, a Mixed-Effects Model was 339

320 points), or always (4 points). The total score can vary used. All analyses were performed on an intention-to- 340

treat (ITT) basis (i.e., all initially randomized patients

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321 between 0 and 88 points. The internal consistency for 341

322 the Brazilian version of the instrument was ␣=0.87 were included in the analysis according to group 342

323 [44]. assignment) and results were reported according to 343

the CONSORT. Figure 1 depicts the CONSORT dia- 344

gram of the study. 345

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RESULTS 346

Of 86 participants initially screened for study eli- 347

gibility, 19 were excluded who did not meet inclusion

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348

criteria and 13 were excluded due to non-interest in 349

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study. 350

Table 1 displays the demographic and clinical 351

characteristics of the patient sample at baseline. 352

This sample is comprised of 54 individuals with 353

dementia and their caregivers that were included in 354

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this trial. Patients with dementia had a mean age 355

of 77.4 years, were predominantly female (66.7%), 356

were under-educated (70.3% with < 8 years of for- 357

mal education), and had moderate dementia (mean 358

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MMSE score of 14.5). Caregivers were predomi- 359

nantly composed of older middle-aged (mean age 360

58.7 years), women (77.8%), and most were a rel- 361

ative of the patient with dementia (81.5%). There 362

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were no statistically significant differences between 363

the experimental and control groups in demographic 364

and clinical variables, except for MMSE scores 365

(p = 0.04) (experimental < control). Table 2 displays 366

demographic of caregivers at baseline. 367

Table 3 provides the changes in NPI-C scores from 368

pre- to post-treatment. The score for each domain was 369

obtained with the sum of clinical impression ratings 370

Fig. 1. CONSORT diagram of the study. for all items, including information about severity, 371
 6 A.M. Oliveira et al. / Randomized Clinical Trial Using an Outpatient Version of Tailored Activity Program

Table 1
Clinical and demographics characteristics of individuals with dementia
Characteristics Total Sample CG EG p∗
(n = 54) (n = 26) (n = 28)
Age (y), mean ± SD 77.4 ± 7.5 76.3 ± 6.6 78.4 ± 8.4 0.32
Gender, n (%) 0.44
Female 36 (66.7%) 16 (61.5%) 20 (71.4%)
Male 18 (33.3 %) 10 (38.5%) 8 (28.6%)
Marital Status, n (%) 0.32

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Married 23 (42.6%) 12 (46.1%) 11 (39.3%)

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Divorced 3 (5.6%) 2 (7.7%) 1 (3.6%)
Single 2 (3.7%) 2 (7.7%) 0 (0%)
Widower 26 (48.1%) 10 (38.5%) 16 (57.1%)
Education Level, n (%) 0.34b
Less than 4 y 14 (25.9%) 8 (30.8%) 6 (21.4%)
4 to 8 y 24 (44.4%) 13 (50%) 11 (39.3%)
More than 8 y 16 (29.6%) 5 (19.3%) 11 (39.3%)

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Living Arrangements, n (%) 0.93
In their own homes 40 (74.1%) 19 (73.1%) 21 (75%)
Living with Family in their homes 14 (25.9%) 7 (26.9) 7 (25%)
Mini-Mental State Exama ; 14.5 ± 4.2 (15) 15.7 ± 4.0 (16.5) 13.4 ± 4.2 (13) 0.04
mean ± SD (median)
Type of Dementia, n (%)∗∗

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0.61
Probable or possible Alzheimer’s disease 49 (90.7%) 23 (88.5%) 26 (92.8%)
Mixed dementia 5 (9.2%) 3 (11.5%) 2 (7.1%)
Number of NPS; mean ± SD 7.8 ± 2.3 7.4 ± 2.3 8.2 ± 2.1 0.16
Type of Medication, n (%) 0.45
AChE inhibitors or memantine 16 (32.6%) 7 (33.3%) 9 (32.1%)
AChE inhibitors or 17 (34.7%)
Au 9 (42.9%) 8 (28.6%)
memantine + antidepressant
AChE inhibitors or 16 (32.6%) 5 (23. 8%) 11 (39.3%)
memantine + antipsychotic medication
CG, Control Group; EG, Experimental Group; SD, standard deviation; ∗ p-value for differences in means (EG versus CG); a Mann-Whitney
test except otherwise indicated (b) ; b Qui-squared test. ∗∗ Diagnostic subtype of dementia according to clinical judgement and/or information
provided by the referring clinician.
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Table 2
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Characteristics of caregivers (total sample and according to control and experimental group)
Characteristics total sample CG EG p
(n = 54) (n = 26) (n = 28)
Age (y), mean ± SD 56.8 ± 14.3 60 ± 13.9 54 ± 14.2 0.12
Gender; n (%) 0.88
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Female 42 (77.8%) 20 (76.9%) 22 (78.6%)

Male 12 (22.2%) 6 (23.1%) 6 (21.4%)
Type of Caregiver, n (%) 0.14
Professional 10 (18.5%) 3 (11.6%) 7 (25%)
Family member 39 (72.2%) 22 (84.6%) 17 (60.7%)
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(wife, child, brother or sister)

Other Relatives (daughter/son in-law; 5 (9.3%) 1 (3.8%) 4 (14.3%)
brother/sister in-law)
CG, Control Group; EG, Experimental Group; SD, standard deviation; ∗ p-value for differences in means.
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372 frequency, and caregiver distress [40, 41]. At base- vocalization’ (Table 3). However, independent sam- 380

373 line, participants in the EG had higher mean values ples T-tests showed that these mean differences 381

374 for 12 out of 14 NPI-C subdomains (‘delusions’, ‘hal- between groups were not statistically significant for 382

375 lucinations’, ‘agitation’, ‘aggression’, ‘depression’, any of the NPI-C subdomains, except for ‘depression’ 383

376 ‘anxiety’, ‘euphoria’, ‘apathy’, ‘disinhibition’, ‘irri- at endpoint (only), where the EG displayed lower 384

377 tability’, ‘motor disturbance’, and ‘sleep disorder’); mean scores after the intervention (p = 0.014); how- 385

378 higher NPI-C sub-scores were only found in the ever, such finding was not supported by Bonferroni 386

379 CG (compared to EG) in ‘appetite’ and ‘aberrant correction.

 A.M. Oliveira et al. / Randomized Clinical Trial Using an Outpatient Version of Tailored Activity Program 7

Table 3
Mean scores in NPI-C subdomains according to study groups at baseline (T0 ) and endpoint (T1 )
NPI-C Group Score T0 ∗ Score T1 ∗ Change (T0 -T1 ) p∗∗ Effect Size∗∗
subdomain mean (SD) mean (SD) mean (SD)
Delusions EG 4.5 (4.2) 3.1 (4.1) 1.2 (3.5) 0.05 0.3
CG 2.5 (3.8) 2.7 (3.8) –0.2 (1.2)
Hallucinations EG 2.5 (2.6) 2.1 (2.8) 0.5 (2.3) 0.06 0.2
CG 1.9 (3.0) 2.5 (3.1) –0.5 (1.1)
Agitation EG 14.3 (8.1) 8.8 (6.5) 5.0 (6.3) 0.001 0.5

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CG 10.1 (8.0) 10.1 (8.6) 0.1 (3.6)

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Aggression EG 5.1 (4.8) 2.8 (3.3) 2.2 (3.3) 0.007 0.4
CG 4.3 (4.7) 4.3 (5.1) –0.1 (2.0)
Depression EG 11.1 (7.6) 5.4 (4.6) 4.3 (6.4) 0.008 0.4
CG 7.8 (5.7) 9.5 (5.6) 0.5 (4.3)
Anxiety EG 11.6 (8.0) 6.8 (7.0) 4.4 (6.2) 0.006 0.4
CG 10.3 (8.8) 10.2 (8.5) 0.1 (4.8)
Euphoria EG 2.1 (2.0) 1.5 (1.9) 0.8 (1.5) 0.007 0.3

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CG 1.7 (3.3) 2.3 (3.5) –0.6 (1.9)
Apathy EG 19.1 (9.0) 15.5 (10.4) 4.0 (9.4) 0.02 0.3
CG 15.7 (9.2) 16.5 (10.3) –0.6 (4.0)
Disinhibition EG 8.2 (5.9) 7.00 (5.9) 1.9 (4.6) 0.03 0.2
CG 7.3 (7.7) 8.4 (7.8) –1.0 (4.3)

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Irritability EG 11.9 (9.4) 7.5 (6.1) 4.1 (7.8) 0.03 0.3
CG 11.0 (9.1) 11.3 (9.7) –0.2 (6.0)
Motor disturbance EG 7.4 (5.6) 4.7 (3.8) 2.6 (5.2) 0.007 0.4
CG 6.4 (5.9) 6.9 (6.3) –0.4 (1.8)
Sleep disorder EG 6.4 (6.8) 4.8 (6.0) 1.6 (4.0) 0.06 0.2
CG 5.9 (6.4) 6.2 (7.2) 0.0 (2.8)
Appetite EG 3.1 (3.2) 3.5 (2.9) –0.3 (3.6) 0.5 0.08
Au
CG 4.1 (4.1) 4.0 (3.8) 0.3 (2.9)
Aberrant EG 2.3 (2.7) 1.4 (1.9) 0.9 (2.0) 0.03 0.3
Vocalization CG 2.8 (3.8) 2.8 (4.1) 0.0 (1.2)
NPI-C, Neuropsychiatric Inventory Clinician Version; EG, experimental group; CG, control group; T0 , baseline (pre-intervention); T1 ,
endpoint (post-intervention); Values presented as means and standard deviations (SD). ∗ Independent samples T-test comparing mean
differences in NPI-C subdomain scores between EG and CG at baseline (T0 ) and endpoint (T1 ) did not show any statistically significant
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differences. ∗∗ Significance levels and effect size relative to group differences in NPI-C changes between T0 and T1 using mixed-effects
model (two leftmost columns).
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Table 4
Means for ZARIT Scale between CG and EG in T0 and T1
Test Symptom Group T0 T1 p∗ Effect Size
(mean; SD) (mean; SD)
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Zarit Caregiver EG 41.3 (18.5) 30.9 (15.6) 0.01 0.4

Scale burden CG 38.8 (18.8) 37.8 (15.0)
CG, control group; EG, experimental group; SD, standard deviation; NPI-C, Neuropsychiatric Inventory Clinician Version; ∗ p value for
differences of means between T0 and T1 .
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387 DISCUSSION non-pharmacological interventions for NPS [7, 27, 398

46, 48]. 399

388 This is the first clinical trial investigating an out- It seems that the engagement in activities tai- 400
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389 patient version of TAP, comparing it with a psychoe- lored to cognitive capacity and interests of dementia 401

390 ducational intervention to treat NPS in Individuals patients reduce some types of behavioral symptoms 402

391 with dementia and caregiver burden. The findings [20, 21, 34, 39]. In the Occupational Therapy inter- 403

392 from this study suggest that activities tailored to inter- vention, we believe activities fill a void, maintain 404

393 ests and cognitive abilities of patients living with roles, and enable dementia patients to express them- 405

394 moderate-to-severe dementia may improve some selves positively. This promotes continuity in identity 406

395 behavioral symptoms replicating, in part, previous and a sense of connectedness and belonging, impor- 407

396 studies about the TAP in-home version [20, 21, tant to quality of life throughout the disease [20, 408

397 35, 40] and being similar to other studies about 21, 32, 34]. By introducing simplified activities that 409
 8 A.M. Oliveira et al. / Randomized Clinical Trial Using an Outpatient Version of Tailored Activity Program

410 capitalized on preserved capabilities and lifelong burden among these subjects. It is possible the psy- 462

411 social roles (e.g., preparing simple meals for home- choeducational intervention offered to participants in 463

412 makers), frustration was minimized, and positive CG helped caregivers to develop a greater awareness 464

413 engagement afforded [32]. Another possible explana- of the condition by providing information about the 465

414 tion is that TAP reduces stress caused by an overload nature of this clinical condition and a better under- 466

415 of sensory and information processing capacity [32]. standing of the characterizations of NPS in dementia; 467

416 The TAP method proposes to simplify the task and as a result, these participants were able to report 468

417 organize the environment where the activities are patients’ symptoms more accurately at the time of 469

f
418 carried out, favoring the reduction of physiological reevaluation (T1). In this case, “worsening” in NPS 470

roo
419 responses to stress and changes in behavior, such as could actually reflect an information bias at the time 471

420 agitation [32]. of the initial assessment (T0). This study replicates, in 472

421 Our results are in line with other studies on non- part, previous studies about the TAP in-home version 473

422 pharmacological interventions for NPS. Chen et al. and non-pharmacological l interventions in reduc- 474

423 [45] showed reduction in the scores of delusions, ing agitation, anxiety [46, 50], and motor disturbance 475

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424 hallucination, and agitation using a combination of [48]. 476

425 activities, including music therapy, motor stimula- Our findings showed that tailored activities did 477

426 tion, and cognitive activities. Svansdottir & Snaedal not have an impact on hallucinations, delusions, or 478

427 [46] found improvement of anxiety, aggression, and eating disorders. According to Brodaty and Burns 479

tho
428 agitation in response to music therapy. [48], hallucinations and delusions are less respon- 480

429 Several studies have suggested that some spe- sive to non-pharmacological interventions than most 481

430 cific types of NPS appear to be more sensitive NPS. Other symptoms such as apathy, agitation, 482

431 to non-pharmacological interventions, mainly, agita- depression, and irritability are thought to be more sus- 483

432 tion, aggression, apathy, depression, sleep disorders, ceptible to non-pharmacological interventions due to 484
Au
433 and irritability [32, 39, 48]. the fact that they are more related to environmental 485

434 Current conceptual models suggest that the pres- than to biological factors [20, 39]. 486

435 ence of NPS is a consequence of vulnerabilities The TAP-O method was effective in reducing 487

436 to physical and social environments due to neuro- caregiver burden. The same result was observed in 488

437 degenerative processes [20, 21]. It seems that tai- previous studies of the TAP in-home method [47, 489

lored activities, in accordance with cognitive aspects 34]. Many studies have demonstrated the importance
d

438 490

439 and previous interests of the individual may mini- of training caregivers—not only regarding NPS, but 491
cte

440 mize these vulnerabilities and help Individuals with also about cognitive deficits, the impact of dementia 492

441 dementia remain physically active and meaningfully on the patient’s abilities, and the level of assistance 493

442 engaged, providing a better quality of life [20, 21, required and provided by the caregiver [51, 52]. Our 494

443 49]. findings suggest that the caregiver’s stress manage- 495

444 The present study also found a reduction in the ment techniques, in addition to the training on routine 496
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445 scores of aberrant motor disorder, aberrant vocaliza- organization, communication techniques, and man- 497

446 tions and agitation in the individuals who received agement of the NPS can reduce caregiver burden 498

447 the intervention. The reduction of these NPS may be [53]. 499

448 explained by the introduction of pleasurable activ- Another positive aspect to be considered is that our 500
co

449 ities in the routine of these individuals, favoring CG was not a “waiting group” (i.e., a group waiting 501

450 their engagement in activities aimed at specific goals, for the intervention in the near future) which is known 502

451 which may provide a decrease in psychomotor hyper- to introduce bias in comparability between groups 503

452 activity [20]. [54]. In the present study, TAP-O was compared to 504
Un

453 Individuals with dementia allocated in the CG the psychoeducative approach, which is widely used 505

454 experienced worsening of symptoms in some NPS and recognized as a support intervention [55]. 506

455 domains, which could be at first interpreted as an We also acknowledge some limitations of the 507

456 effect of the progression of the neurodegenerative present study. First, one should expect that the inclu- 508

457 process. Our results suggest that TAP-O intervention sion of subjects (patient-caregiver pairs) to participate 509

458 is superior to psychoeducation to reduce these symp- in a hospital-based clinical study using a rather com- 510

459 toms. It is interesting to note that, although there was plex intervention protocol may select participants 511

460 a worsening in the NPI-C scores among the partici- with particular needs and resources, therefore lim- 512

461 pants in the CG, there was no worsening of caregiver iting the generalizability of the present findings. 513
 A.M. Oliveira et al. / Randomized Clinical Trial Using an Outpatient Version of Tailored Activity Program 9

514 Actually, there were difficulties regarding the recr- completion of the study. Another possible limitation 566

515 uitment of patients and caregivers, as follows: 1) refers to the occurrence of education bias. Education 567

516 individuals with moderate to severe dementia had dif- level was obtained as a categorical variable, indicat- 568

517 ficulties with mobility; and 2) availability of patients ing attainment levels (incomplete elementary school; 569

518 and caregivers to attend the clinic every week, for a complete elementary school; secondary schooling or 570

519 three-month period. Also, the present study was con- higher) and not as a continuous variable. Differences 571

520 ducted in a rather heterogeneous sample of patients in the distribution of these categories of education 572

521 with dementia, which means that the diagnosis was level across groups were not statistically significant; 573

f
522 syndromic, and was by no means restricted to a however, the EG had a larger proportion of sub- 574

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523 particular etiology. Most patients had clinical presen- jects with more than 8 years of education, although 575

524 tation compatible with probable or possible AD, or presenting with lower mean MMSE scores, as com- 576

525 mixed dementia (AD with cerebrovascular disease), pared to the CG. We understand that any differences 577

526 but a few patients presented symptoms compatible in education status might be dissipated by the fact 578

527 frontotemporal dementia or dementia with Parkin- that the prescribed TAP activities do not require the 579

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528 sonism. This could be viewed as a limitation of integrity of instrumental abilities and are adjusted to 580

529 the study design, or, conversely, as an advantage, the patient’s global cognitive state as defined at base- 581

530 given the broader and unspecific needs of people line. In this sense, differences in MMSE observed 582

531 with dementia and their caregivers, when dealing between EG and CG (the former having lower mean 583

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532 with behavioral abnormalities, irrespective of its eti- scores) are conservative to the interpretation of the 584

533 ology. In this study, we did not intend to evaluate study results, i.e., in spite of having a slightly worse 585

534 the effectiveness of the intervention according to the MMSE performance at baseline, subjects in the EC 586

535 etiology of dementia. Rather, patients were enrolled had a better outcome from the TAP intervention. 587

536 if they had a syndromic diagnosis of moderate to Likewise, a possible randomization bias may have 588
Au
537 severe dementia according to MMSE scores. It is also resulted in discrepancies in the composition of 589

538 likely that a proportion of cases clinically described groups regarding the severity of behavioral impair- 590

539 as having AD would in fact have underlying sub- ment at baseline, EG displaying higher morbidity 591

540 cortical vascular pathology, at different levels. We than CG according to NPI-C subdomains, although 592

541 understand that this situation is compatible with what these differences were not statistically significant. 593

we find in clinical practice, where dementia patients Anyhow, such discrepancies did not prevent the EG
d

542 594

543 normally display mixed pathologies, in spite of hav- from having a better profile of changes from baseline 595
cte

544 ing a presumptive clinical diagnosis of possible or as an effect of the intervention. 596

545 probable AD. However, all participants had medi- Finally, our data supports that the TAP-O is an 597

546 cal reports with the diagnosis of dementia and had effective alternative to its home-based version mainly 598

547 MMSE scores < 20 at the time of screening. Accord- for occupational therapists who live in large cities 599

548 ing to the systematic review by Creavin et al. [56], where home care is difficult due to long distances 600
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549 the specificity of MMSE to diagnose dementia is con- and traffic issues that might hamper agility in assis- 601

550 sidered high, between studies, ranging from 0.85 to tance. Furthermore, for occupational therapists who 602

551 0.97. Thus, MMSE criteria may provide confirma- work within rehabilitation settings, the TAP-O rep- 603

552 tion of the diagnosis of moderate to severe dementia. resents a different paradigm from curative/learning 604
co

553 The heterogeneous sample, on the other hand, may to compensatory/palliative support, with an emphasis 605

554 be considered evidence that the TAP-O method pro- on engagement in meaningful and adapted activities. 606

555 vides clinical benefits regardless of the nature of the

556 dementia. Future studies are necessary and to estab-
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557 lish the specificity of the method in dementia of CONCLUSION 607

558 different etiologies. All patients throughout the study

559 were on stable use of anti-dementia medications for This clinical trial is the first controlled study to 608

560 at least 60 days prior to enrollment. This requirement address the effectiveness of an occupational therapy 609

561 was adopted to minimize the confounding effect of intervention based on the outpatient version of the 610

562 medications on NPS. This piece of information was TAP method to reduce some NPS in patients with 611

563 provided by caregivers and monitored by our clin- moderate to severe dementia. This study contributes 612

564 ical team, to ensure that there were no alterations to the growing body of evidence reinforcing the effec- 613

565 in the prescription of psychotropic drugs until the tiveness and benefits of occupational therapy in the 614
 10 A.M. Oliveira et al. / Randomized Clinical Trial Using an Outpatient Version of Tailored Activity Program

615 multidisciplinary management of vulnerable individ- symptoms of dementias with psychopharmaceuticals: A 669

616 uals with dementia and their caregivers. review. Neuropsychiatr Dis Treat 9, 1211-1220. 670
[8] Geda YE, Roberts RO, Knopman DS, Petersen RC, Chris- 671
617 Our results also confirm other similar studies about tianson TJ, Pankratz VS, Smith GE, Boeve BF, Ivnik RJ, 672
618 non-pharmacological intervention in the treatment of Tangalos EG, Rocca WA (2008) Prevalence of neuropsy- 673

619 NPS in individuals with dementia, but it is expected chiatric symptoms in mild cognitive impairment and normal 674

620 that future studies will contribute to explaining the cognitive aging: Population-based study. Arch Gen Psychi- 675
atry 65, 1193-1198. 676
621 neurobiological mechanisms which are related to tai- [9] Gauthier S, Cummings J, Ballard C, Brodaty H, Grossberg 677
622 lored activities and neuropsychiatric symptoms. G, Robert P, Lyketsos C (2010) Management of behav- 678

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ioral problems in Alzheimer’s disease. Int Psychogeriatr 22, 679

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346-372. 680
623 ACKNOWLEDGMENTS [10] Hashimoto M, Yatabe Y, Ishikawa T, Fukuhara R, Kaneda 681
K, Honda K, Yuki S, Ogawa Y, Imamura T, Kazui H, 682

624 The Laboratory of Neuroscience (LIM-27), Uni- Kamimura N, Shinagawa S, Mizukami K, Mori E, Ikeda M 683
(2015) Relationship between dementia severity and behav- 684
625 versity of Sao Paulo, receives financial support from ioral and psychological symptoms of dementia in dementia 685
the Alzira Denise Hertzog Silva Association (ABA

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626 with Lewy bodies and Alzheimer’s disease patients. Dement 686

627 DHS), Instituto Nacional de Biomarcadores em Geriatr Cogn Dis Extra 6, 244-252. 687

628 Neuropsiquiatria (INBION), Sao Paulo Research [11] Phan SV, Osae S, Morgan JC, Inyang M, Fagan SC 688
(2019) Neuropsychiatric symptoms in dementia: Consid- 689
629 Foundation (FAPESP; Projects 09/52825-8, 2014/ erations for pharmacotherapy in the USA. Drugs R D 19, 690
630 14211-6, 2016/01302-9) and National Council for 93-115. 691

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631 Scientific and Technological Development (CNPq; [12] Gitlin LN (2012) Good news for dementia care: Care- 692

632 Projects 442795/2014-9 and 466625/2014-6). giver interventions reduce behavioral symptoms in people 693
with dementia and family distress. Am J Psychiatry 169, 694
633 Authors’ disclosures available online (https:// 894–897. 695
634 www.j-alz.com/manuscript-disclosures/21-0142r2). [13] Landes AM, Sperry SD, Strauss ME (2005) Prevalence of 696
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