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Psychotropic drugs in Alzheimer’s disease: a longitudinal study by the Registry of

Dementias of Girona (ReDeGi) in Catalonia (Spain)

Authors

Laia Calvó-Perxas1, Oriol Turró-Garriga1, Maria Aguirregomozcorta2, Josep Bisbe3,

Erélido Hernández4, Secundino López-Pousa1,5,6, Anna Manzano7, Mónica Palacios8,

Imma Pericot-Nierga5, Héctor Perkal9; Lluís Ramió10, Joan Vilalta-Franch1,5,6, Josep

Garre-Olmo1,6 on behalf of the Registry of Dementia of Girona Study Group (ReDeGi

Study Group)

Affiliations:

1Institute of Biomedical Investigation of Girona (IdIBGi), IAS Research Unit, Salt,

Catalonia (Spain); 2Neurology Unit, Hospital de Figueres, Figueres, Catalonia (Spain);

3Neurology Department, Hospital d’Olot, Olot, Catalonia (Spain); 4Dementia Unit,

Serveis de Salut Integrats del Baix Empordà, Palamós, Catalonia (Spain); 5Dementia

Unit, Hospital de Santa Caterina, Salt, Catalonia (Spain); 6Department of Medicine,

University of Girona, , Catalonia (Spain); 7Neurology Department, Hospital de

Campdevànol, Campdevànol, Catalonia (Spain); 8Pharmacy Unit, Health Region of

Girona, Catalonia (Spain); 9Geriatrics and Neurology Department, Hospital de Blanes,

Blanes, Catalonia (Spain); 10Neurodegenerative Disease Unit, Hospital Universitari Dr.

Josep Trueta, Girona, Catalonia (Spain).

Author of correspondence: Oriol Turró-Garriga. Institute of Biomedical Investigation

of Girona (IdIBGi), IAS Research Unit. Address: C/ Dr. Castany s/n. 17190 Salt.

Girona. Phone: 972182600 ext.1830. E-mail: recerca@ias.scs.es

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The ReDeGi Group consists of the following investigators:

Department of Neurology, Hospital Universitari Josep Trueta: Mar Castellanos;

David Genís Batlle; Jordi Gich; Albert Molins; Lluís Ramió; Joaquín Serena; Yolanda

Silva.

Dementia Unit, Hospital Santa Caterina: Marta Hernández; Saioa Lejarreta; Manuela

Lozano; Immaculada Pericot; Joan Vilalta-Franch; Antoni Turon Estrada; Josefa

Turbau; Jordi Llinàs; Secundino López-Pousa.

Dementia Unit, Serveis de Salut Integrats del Baix Empordà: Elisabet Alsina; Rosa

de Eugenio; Erélido Hernández; Margarita Flaqué.

Neurology Department, Hospital de Figueres: Olga Carmona; Marta Cullell; Teresa

Osuna; Maria Aguirregomozcorta; Mª del Mar Fernández.

Neurology and Geriatrics Departments, Hospital d’Olot: Josep Bisbe; Marta

Linares; Fabian Marquez Daniel; Natalia Vallmajó.

Neurology and Geriatrics Departments, Hospital de Blanes: Fernando Espada;

Teresa Casadevall; Héctor Perkal; Marta Viñas.

Neurology Department; Hospital de Campdevànol: Isabel Casas; Josefa Turbau;

Josep Mª Cuy; Anna Manzano.

Pharmacy Unit, Healh Region of Girona: Anna Maria Roig; Joan Coromina; Mònica

Palacios Soto.

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Abstract

Objectives: Psychotropic drugs are usually prescribed to deal with Behavioral and

Psychological Symptoms of Dementia (BPSD), especially when non-pharmacological

approaches are not available or have limited efficacy. Poor outcomes, and serious

adverse events of the drugs used must be addressed, and risk-benefit ratios need to be

considered. The aim of this longitudinal study was to describe the evolution of

dispensation of psychotropic drugs in patients with Alzheimer’s disease (AD), and to

identify the associated demographic and clinical variables. Design and measurements:

Longitudinal study using 698 cases with AD included in the Registry of Dementias of

Girona (ReDeGi) in 2007 and 2008, and followed up during three years. Drugs were

categorized according to the ATC classification. Binary logistic regression analyses

were used to detect the variables associated with the use of antipsychotics, selective

serotonin reuptake inhibitors (SSRIs), anxiolytics, and hypnotics and. Results: 51.2% of

the patients consumed antipsychotics at least once during the three years of the study,

while 73.3% and 58.2% consumed SSRIs and anxiolytics, respectively, and 32.8% used

hypnotics. Antipsychotic use was associated with a diagnosis of AD with delusions

(ADdel) (OR=5.7) and with increased behavior disorders (OR=1.2). Patients with AD

with depressed mood (ADdep) were more likely to be treated with SSRIs (OR=3.1),

while being a woman was associated with increased dispensation of anxiolytics

(OR=1.9) and SSRIs (OR=2.2). Conclusion: Consumption of psychotropic drugs by the

patients with AD registered in the ReDeGi is very high. Despite all the described

adverse effects and recommendations of caution in their use, antipsychotics still are

extensively used.

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Introduction

Behavioral and psychological symptoms of dementia (BPSD) are displayed by 60-98%

of the patients with dementia1,2, and may include a wide variety of symptoms like

depressive mood, anxiety, hallucinations, and sleep disorders, among others3.

When it comes to deal with BPSD, despite the lack of consistent evidence of efficacy, it

is often recommended to consider non-pharmacological interventions before

pharmacologic ones4-7. Nevertheless, knowledge and training on non-pharmacological

treatments is sometimes limited, interventions are not always available, efficacy is

modest, and patient’s adherence is low in many cases7,8. Thus, all these reasons lead to

the pharmacological management of BPSD.

The most widely used psychotropic drugs to treat BPSD in Alzheimer’s disease (AD)

include antipsychotics, antidepressants, anxiolytics, and hypnotics, although benefits in

behavior are also expected when prescribing anti-dementia medication4,8-10.

According to Selbaek et al.11, most BPSD show an intermittent course, with regressions

and relapses. Also, most BPSD such as behavioral and psychotic symptoms, increase

frequency and intensity as the dementia progresses12,13. This seems to be especially true

regarding hallucinations, which usually resolve over a few months, while delusions or

agitation show more stable patterns5. This intermittent course does not support long-

term treatments, especially with drugs showing severe adverse effects or even increased

mortality risk, such as antipsychotics5,14-16.

To our knowledge, most of the studies carried out so far describing the use of

psychotropic drugs in patients with dementia, are performed in nursing home

residences10,17,18, include only patients living in the community19, or study particular

drugs, specific BPSD, and/or use the information contained in administrative

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databases20-24. These studies usually have low external and internal validity, mainly due

to the selection bias of the sample, and/or to the low reliability of administrative

databases. In contrast, the data collected by an epidemiological surveillance system

focused on dementia, combined with the information on drugs use obtained from a drug

prescription database provides detailed and reliable information on the drugs used, and

on the sociodemographical and clinical characteristics of the patients treated25. This

methodological approach has been useful to estimate the clinical incidence of young

onset dementia in a defined general population26.

The aim of this study is to describe the course of the use of antipsychotics, anxiolytics,

hypnotics, and selective serotonin reuptake inhibitors (SSRIs) in patients with AD along

three years after being diagnosed, and to identify the sociodemographic and clinical

characteristics of the patients consuming each drug, using the available information

from the Registry of Dementias of Girona (ReDeGi), an epidemiological surveillance

system of dementia.

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Methods

Design, geographical area of reference and study population

This study used a longitudinal design and was based on data from the cases registered

by Registry of Dementias of Girona (ReDeGi) in 2007 and 2008. Their psychotropic

drugs consumption was recorded and followed up for three years, which is until 2010

for the cases registered in 2007, and until 2011 for the cases registered in 2008. The

ReDeGi registers demographic and clinical data of all the new dementia cases

diagnosed in the hospitals of the public health care system of the Health Region of

Girona (HRG). The HRG is located in the North-East of Catalunya, which is, in turn, in

the North-East part of Spain. It has an area of 5,517 km2, a population of 761,627

inhabitants (according to the Citizens Municipal Registry 2012), and a population

density of 137.2 inhabitants/km2.

Demographic and clinical information is recorded by the ReDeGi in the year of the

diagnosis. In this study, the medication dispensed to the patients was recorded every

year, for three years, after the diagnosis of dementia was made. Only the cases with AD

for which we had information on drugs dispensation during the three years were

included in this study.

Registry procedure and registered variables

The ReDeGi registers all the incident cases of dementia diagnosed in the 7 hospitals

belonging to the HRG, using standardized criteria for case definition, and following the

guidelines proposed by the Center for Disease Control and Prevention for a surveillance

system27. The methodological principles and the functional structure of the ReDeGi

have been previously described28. All diagnoses are based on an interview with the

patient and the caregiver, a general medical examination, hematology and blood

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chemistry tests, and neuroimaging diagnosis if required. An specialist technician of the

ReDeGi periodically reviews the medical chart of the cases of dementia notified in each

of the 7 hospitals of the HRG, and registers the information in a clinical research form

containing: 1. Center identification, date of admission and clinical history identification

number; 2. Socio-demographical characteristics; 3. Characteristics of the diagnosis

based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)29, date

of onset of the symptoms, date of diagnosis; 4. Clinical characteristics (date of

administration and punctuation of the Mini-Mental State Examination (MMSE)30, the

Blessed Dementia Rating Scale (BDRS)31 which consists of three sections: changes in

activities of daily living, in habits, and in personality), and the Clinical Dementia Rating

(CDR)32, familiar history of dementia, diagnose of hypertension, diabetes mellitus,

dyslipidemia, cerebro-vascular adverse events, thyroid disease, depression history, or

personal history of psychosis (delusions and hallucinations occurring before the

diagnose of dementia). The collected information of the ReDeGi meets the

confidentiality requirements stated by the Spanish legislation.

Alzheimer’s disease subtypes

In this study we used the DSM-IV classification in order to distinguish among three

different subtypes of AD: uncomplicated Alzheimer’s disease (uAD) (DSM-IV codes

290.0, and 290.10), Alzheimer’s disease with depressed mood (ADdep) (DSM-IV codes

290.21, and 290.13), and Alzheimer’s disease with delusions (ADdel) (DSM-IV codes

290.20, and 290.12).

Drug dispensation information

The ReDeGi database was linked with the HRG Pharmacy Unit database from the

Public Catalan Healthcare Service (PCHS). The drugs dispensed to the patients included

in the ReDeGi were longitudinally recorded, from the year the diagnosis was made

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(2007 or 2008), every year, until three years later (2010 or 2011). Information on drugs

use was annually collected, regardless of non-adherence or treatment withdrawal. The

database of the HGR Pharmacy Unit contains all the drugs prescribed by the PCHS

professionals that have been dispensed in pharmacies. Patient records were linked using

the personal identification code included in their medical chart. All drugs were provided

by the PCHS database at 7th level Anatomical Therapeutic Chemical (ATC)

classification system. The drugs and ATC codes included in this study are listed in

Annex 1.

Data Analysis

A descriptive analysis of the variables was performed using central tendency measures

and dispersion for quantitative variables. Absolute and relative frequencies were

calculated for qualitative variables. Normality was checked using Shapiro-Wilk test33.

The clinical and demographic characteristics between the cases diagnosed with uAD,

ADdep, and ADdel were compared using χ2 tests for categorical variables and Kruskal-

Wallis tests for continuous variables. Pairwise group comparisons were considered

significant if p<0.005 after Bonferroni adjustment for multiple comparisons. Chi-square

tests and Mann-Whintney’s U test were used to analyze the characteristics of the

patients who had been dispensed antipsychotics, anxiolytics, hypnotics, and sedatives.

Four different binary logistic regression models were performed to detect the main

variables related to the annual prescription, for 36 months (3 years), of antipsychotics,

anxiolytics, hypnotics, and SSRIs. All the models included as covariables: sex, age,

education, civil status, residence, MMSE score, BDRS scores, CDR, and subtype of

dementia. The Hosmer-Lemeshow test was used to test goodness of fit of the models.

Results are expressed as absolute numbers and percentages, means, standard deviations,

odd ratios, and 95% confidence intervals (CI). Statistical tests were considered to be

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significant with a two-tailed p value <0.05. Processing and analysis of the data were

performed using the statistical package SPSS v15.0 for Windows (SPSS, Inc., Chicago,

IL).

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Results

Study population characteristics

A total of 773 AD cases were registered by the ReDeGi in 2007 and 2008. Information

on drugs dispensation during the three years of this study was available for 698 cases

(90.3%). Of these, 75.9% (n=530) cases had uncomplicated AD (DSM-IV codes 290.0,

and 290.10), 13.5% (n=94) cases had AD with depressed mood (DSM-IV codes 290.21,

and 290.13), and 10.6% (n=74) cases had AD with delusions (DSM-IV codes 290.20,

and 290.12). The mean age was 79.8 (SD=6.6) years, and 67.0% (95% CI: 63.5-70.6)

were women. Only 9.7% (95% CI: 7.4-12.0) had a severe dementia (CDR=3), 26.0%

(95% CI: 22.7-29.4) were moderate (CDR=2), and 64.3% (95% CI= 60.7-67.9) were

mild (CDR=1). Regarding the residence, only 8.4% (95% CI= 6.2-10.6) of the cases

were institutionalized at the moment of diagnosis. The frequency of severe dementias in

the cases living in nursing home residences was 29.2% (95% CI: 17.4-41.1), whereas

only 4.5% (95% CI: 2.4-6.6) of the patients living at home or with the family had severe

dementia. Along the three years of the follow-up, most of the cases (90.1%; 95% CI=

87.4-92.7) consumed anti-dementia drugs. The main socio-demographical and clinical

characteristics of the cases depending on the subtype of AD are described in Table 1.

Dispensation of antipsychotics, SSRIs, anxiolytics, and hypnotics

Of all the cases, 51.2 % (95% CI: 46.9-55.6) have been dispensed an antipsychotic, at

least once, during the three years of the study, and most of them had ADdel (80.4%

ADdel vs. 47.1% uAD and 55.0% ADdep; χ2=18.870; df=2; p<0.001). Moreover,

antipsychotics were prescribed every year, during the 3 years of this study, to 12.7%

(95% CI: 9.7-15.6) of the cases, and, also in this case, the patients having ADdel used

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an antipsychotic more often than the patients diagnosed with other AD subtypes (41.3%

of ADdel vs. 9.6% of uAD and 11.3% of ADdep; χ2=37.559; df=2; p<0.001).

Regarding SSRIs, they were dispensed at least once during the three years of the study

in 73.3% (95% CI: 69.4-77.2) of the cases, and patients with uAD used them less

frequently (69.4% uAD vs. 88.8% ADdep and 80.4% ADdel; χ2=14.082; df=2;

p=0.001). SSRIs were prescribed every year, during the 3 years of this study, to 40.7%

(95% CI: 36.4-45.0) of the patients, and in this case, patients with ADdep presented a

higher frequency of dispensation during the three years than the rest of the patients

(61.3% of ADdep vs. 37.0% of uAD and 37.0% of ADdel; χ2=16.553; df=2; p<0.001).

More than half of the registered cases used anxiolytics at least once during the three

years of the study (58.2%; 95% CI: 53.8-62.5), and 20.9% (95% CI: 17.3-24.5) used

them along the three years. In the case of hypnotics, they were prescribed at least once

to 32.8% of the patients (95% CI: 28.7-36.9), and only 7.1% (95% CI: 4.8-9.4) used

them along the three years. There were no differences in the dispensation of anxiolytics

and hypnotics depending on the subtype of AD.

Figure 1 depicts the longitudinal dispensation of antipsychotics, hypnotics, anxiolytics,

and SSRIs according to the subtype of AD.

In relation with sociodemographic and clinical variables, institutionalized patients were

more often prescribed, every year, during the three years of the study, antipsychotics

(28.9% vs 11.6%; χ2=9.336; df=1; p=0.005), and anxiolytics (34.2% vs. 20.0%;

χ2=4.288; df=1; p=0.036). The same happened with patients with higher BDRS scores

(Antipsychotics: BDRS cognitive 4.1 vs. 3.3 points; Mann-Whitney’s U=8836.00;

p<0.001; BDRS functional 1.3 vs 0.8 points; Mann-Whitney’s U=10889.00; p=0.006;

BDRS behavior 3.4 vs 2.6 points; Mann-Whitney’s U=10219.00; p=0.003. Anxiolytics:

BDRS functional 1.1 vs 0.8 points; Mann-Whitney’s U=16378.00; p=0.004; BDRS

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behavior 3.1 vs 2.6 points; Mann-Whitney’s U=16455.00; p=0.019). Antipsychotics

were also more often dispensed to those with moderate and severe dementias (23.5%

CDR=2, 23.1% CDR=3 vs. 8.3% CDR=1; χ2=22.057; df=2; p<0.001), and regarding

SSRIs, they were more often dispensed to women (43.9% vs 34.1%; χ2=4.518; df=1;

p=0.021).

Multivariate models

Four binary logistic regression models adjusted for the main socio-demographical and

clinical variables were performed. The consumption of antipsychotics, anxiolytics,

hypnotics, and SSRIs every year, during the three years of study, was used as the

dependent variable (Table 2) in each case. Results show that patients with ADdel and

ADdep are more prone to continuously receive antipsychotic and SSRI treatment,

respectively. Women are more likely to be prescribed anxiolytics, and those with

behavioral symptomatology have increased chance to be treated with antipsychotics and

anxiolytics. Finally, living in a nursing home is associated with an increased intake of

anxiolytics.

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Discussion

In this paper we describe the use of antipsychotics, SSRIs, anxiolytics, and hypnotics,

by the patients with AD registered by the Registry of Dementias of Girona (ReDeGi)

during three years. We also identified the demographic and clinical variables related to

the annual use of these drugs, along three years.

Although it is a matter of debate8, anti-dementia drugs have been reported to show

moderate efficacy to treat BPSD4,5,9-10. Memantine may reduce agitation and

aggression24, and cholinesterase inhibitors may have some effect, in decreasing apathy,

depression, and aberrant motor behavior5. In Spain, anti-dementia treatment is

prescribed by the public health service to all patients with AD who may benefit from it.

Thus, except in cases with contraindications, intolerances, or non-adherence, most of

the AD patients in our study (>90%) were treated with, at least, one anti-dementia drug.

According to our results, the frequency of at least one antipsychotic prescription

during the three years of our study was high (51.2%), but in agreement with other

population studies carried out in our country (45.2%)34 and in the Netherlands (42%)10.

However, our result was higher than what has been recently reported by Gustafsson et

al.9 in specialized care units (38%). In our study, 12.7% of the patients were treated with

an antipsychotic the three years of the study, which is in line with the results obtained

by Wetzels et al.10, although they had a limited sample after two years of follow-up.

Due to the design of our study, we cannot conclude that 12.7% of the patients were

treated with antipsychotics continuously during three years, but if we assumed so, this

frequency would be lower than the 23.3% recorded by Gustafsson et al.9 as long-term

users of antipsychotics. Yet, Gustafsson’s et al.9 follow-up was of 6 months, and we

collected information on drug dispensation during three years, which might explain the

differences. In any case, long term treatments are not supported by the fact that most

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BPSD show an intermittent course11, and although several recent studies have also

published inappropriate long-term use of antipsychotics in patients with dementia9,11,35,

a recent review suggested that old patients with dementia should be withdrawn from

long-term antipsychotic medication, and that discontinuation programs should be

incorporated into clinical practice, always with caution in cases with more severe

BPSD36.

The patients diagnosed with ADdel were more frequently treated with an

antipsychotic, which was expected due to the psychotic nature of the BPSD presented

by this subtype of AD. This is supported by the multivariate analysis, where both the

subtype of dementia (OR=5.7) and behavior disorders (OR=1.2) were associated with

antipsychotic dispensation. According to Cornegé-Blokland et al.20 the main reasons for

starting antipsychotic therapy are agitation and aggression. Some antipsychotics

(aripiprazole, risperidone and olanzapine) seem to have the best evidence-base for

effectiveness compared to placebo, for physical aggression, agitation and

psychosis5,37,38, but they are associated with serious adverse events (accelerated

cognitive decline, extrapyramidal and metabolic side-effects, falls, etc.), and even with

an increased mortality risk5,14-16. Some of the potential pharmacological alternatives to

the use of antipsychotics include anticonvulsants (valproate and carbamazepine)23, but

due to the lack of effectiveness in some clinical trials, increased adverse effects and

drug-drug interactions they are not recommended for routine use to manage

BPSD22,24,39. None of the patients included in our study was treated with valproate at the

time the diagnosis was made, and less than 1% (data not shown) was consuming

carbamazepine. The frequency of a moderate-severe stage of the dementia was higher in

ADdel patients in our study, and although dementia severity was associated with higher

antipsychotic consumption in a cross-sectional study including all the patients in the

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ReDeGi40, this association was not observed in the present longitudinal analysis.

Likewise, the percentage of institutionalized patients in our sample was low, and we did

not detect an association between institutionalization and an increased consumption of

antipsychotics, while other studies conducted in our country did so34.

Concerning antidepressants, almost three out of every four patients in our study were

treated, at least once, with SSRIs, which is much higher than the 24-25% reported in

nursing home residents with dementia from the USA and the Netherlands10,18, and the

43.7% described in our country by Fort et al.34. Also, 40% received an SSRI every year

during the three years of the study, while only 12.8% had a long-term use of

antidepressants in the study by Wetzels et al.10. Major depression may be less frequent

in patients with severe dementias, as reported by Lopez et al.41. Institutionalized patients

usually have more severe dementias, and in our sample, most of the cases had

mild/moderate dementia, which may explain the observed differences. As expected,

patients with ADdep were more frequently prescribed an SSRI than the rest of the

patients, which is reasonable after many studies indicating that they are safe and

effective to treat depression in AD39. Moreover, our multivariate analysis revealed that a

diagnosis of ADdep was associated with the dispensation of SSRIs with an OR=3.1.

However, patients with ADdel and uAD also presented very high frequencies of

dispensation of SSRIs. Among antidepressants, selective serotonin reuptake inhibitors

(SSRIs) are recommended as first line treatment not only for depression, but also for

agitation, aggression24,42, psychosis42, irritability, and anxiety43,44 in dementia. However,

although some SSRIs have shown positive efficacy in various studies5, evidence is still

weak, and larger samples are needed to establish both safety and efficacy of these

treatments42. According to the multivariate analysis, women were more frequently

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treated with SSRIs than men (OR=2.2), which is in agreement with women presenting

an increased prevalence of depression in general population45 and in dementia19.

Regarding anxiolytics and hypnotics, our results suggest much higher frequencies of

consumption than what was reported by other authors10, which may be due to the longer

time of follow-up of our study. Sleep problems are highly prevalent in AD patients5,46,

and are estimated to occur in as much as 25-54% of the patients, which may explain the

frequency of use of hypnotics that we detected. Anxiolytics are often used to reduce

agitation in dementia, and although they are generally safe in lower doses, it is

recommended to use only short acting anxiolytics (and benzodiazepines in general), and

only on as-needed basis39. This would suggest that, regarding anxiolytics and hypnotics,

we may be detecting isolated uses of these drugs, instead of a continuous use along

three years. In the multivariate analysis, patients living in nursing homes (OR=3.3) and

women (OR=1.9) were more prone to be dispensed an anxiolytic. In this sense, cases

with more severe dementias may display more frequent and intense BPSD12, and BPSD

often precipitate institutionalization47 and may lead to increased anxiolytics

prescription. Regarding gender, women in general population tend to report higher

levels of anxiety and are at increased risk for many anxiety disorders48, which may be

the case of women with AD too.

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Conclusion

To conclude, psychotropic medications prescribed to the cases with AD in the ReDeGi

were in concordance with the subtype of dementia diagnosed, and with clinical and

sociodemographic information, which provides evidence of the quality and reliability of

the data included in the ReDeGi. Dispensation rates were found to be very high, which

should be taken into consideration in the light of all serious adverse events, drug-drug

interactions and clinical guides’ recommendations published to date.

There are some limitations to take into account when interpreting the results. First, a

major limitation is that we do not have information on the dosages prescribed or the

duration of the treatments, which prevented the calculation of the defined daily doses

for each drug. Second, we do not have information on adherence, or treatment

withdrawal caused by intolerance. Third, we do not have information on mortality, so

we only used data from patients who stayed alive during the three years of the study,

which may have biased the results. Fourth, regarding BPSD, we only have the

information provided by the behavioral section of the BDRS, and more precise

information may provide new perspectives to our results. Fifth, trazodone was

consumed by almost 15% of the patients in this study (data not shown), but was not

included in this study due to the fact that it although it is classified as an antidepressant,

it is mostly prescribed as an anxiolytic/hypnotics/sedative. Sixth, sociodemographical

data are only collected when the case is registered, at baseline. Future studies should

consider performing a clinical and sociodemographic follow up of the patients. Future

studies on the drug consumption of the patients in the ReDeGi will include both drug

costs, and mortality data, which will allow the formulation of economical predictions,

and the assessment of mortality risks.

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Acknowledgements

* Study group for the Girona Registry of Dementias: Hospital Universitari Josep

Trueta: Mar Castellanos, Jordi Gich, David Genís, Rosa Meléndez, Albert Molins,

Lluís Ramió, Joaquín Serena, Yolanda Silva; Hospital Santa Caterina: Marta

Hernández, Saioa Lejarreta, Manuela Lozano, Imma Pericot, Antoni Turon, Oriol Turró,

Joan Vilalta-Franch; Hospital Comarcal de Palamós: Elisabet Alsina, Rosa De Eugenio,

Margarita Flaqué, Erélido Elígio Hernández; Hospital Comarcal de Figueres: Olga

Carmona, Marta Cullell, Mª del Mar Fernández, Maria Aguirregomozcorta, Teresa

Osuna; Hospital Comarcal Sant Jaume d’Olot: Josep Bisbe, Marta Linares, Fabià

Márquez, Natàlia Vallmajó; Hospital Comarcal de Blanes: Teresa Casadevall, Fernando

Espada, Héctor Perkal, Marta Viñas; Hospital Comarcal de Campdevànol: Isabel Casas,

Josefa Turbau

Conflicts of interest: None

Study funding: The ReDeGi is founded by the Health Region of Girona from the

Department of Health of the Generalitat de Catalunya (Spain). The funding source had

no involvement in the decision to submit the paper for publication.

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Table 1. Sociodemographic and clinical characteristics of the dementia patients

registered in the ReDeGi in 2007 and 2008.

uAD (n=530)

ADdep (n=94)

ADdel (n=74)

Age, mean (SD)* 79.8 (6.5) 77.9 (6.9) 81.6 (6.6)

Sex, n (%) Women 345 (65.1) 71 (75.5) 52 (70.3)

Marital

status, n (%)a

Single/Separated/Widower 249 (50.5) 45 (48.9) 42 (60.9)

Married 244 (49.5) 47 (51.1) 27 (39.1)

Education, n (%)a < 6 years 220 (44.0) 45 (50.0) 35 (51.5)

6-12 years 266 (53.2) 43 (47.8) 31 (45.6)

> 12 years 14 (2.8) 2 (2.2) 2 (2.9)

Residence, n (%)b Community dwelling 461 (91.7) 86 (95.6) 61 (85.9)

Institutionalized 42 (8.3) 4 (4.4) 10 (14.1)

MMSE, mean (SD)* 17.1 (5.2) 17.6 (4.6) 14.8 (5.3)

BDRS, mean (SD) Functional* 1.0 (1.7) 0.4 (1.0) 1.6 (2.0)

Cognitive* 3.4 (1.6) 3.1 (1.5) 4.7 (1.6)

Behavior 2.7 (2.0) 3.1 (1.7) 3.3 (1.9)

CDR score, n (%)c* Mild 346 (65.8) 71 (77.2) 28 (37.8)

Moderate 126 (24.0) 16 (17.4) 38 (51.4)

Severe 54 (10.3) 5 (5.4) 8 (10.8)

Anti-dementia drugs intake, n (%)d 354 (89.2) 79 (97.5) 39 (84.8)

*Bonferroni adjusted p<0.005. MMSE: Mini Mental State Examination; BDRS: Blessed Dementia Rating Scale; CDR: Clinical Dementia Rating; uAD: uncomplicated Alzheimer’s disease; ADdep: Alzheimer’s disease with depressed mood: ADdel: Alzheimer’s disease with delusions amissing information for 40 cases. bmissing information for 34 cases. cmissing information for 6 cases. dmissing information for 174 cases

26  

Table 2. Odds ratio of the variables in multiple logistic regression models. The dependent variable used in each case was antipsychotics,

anxiolytics, hypnotics and selective serotonin reuptake inhibitors (SSRI) dispensation in each of the three studied years.

Wald df p OR IC 95% Hosmer-Lemeshow test

Antipsychotics dispensationBDRS behavior 4.483 1 0.034 1.202 1.014-1.425

χ2=5.6; df=8; p=0.696 ADdel 17.439 1 <0.001 5.695 2.517-12.886

Anxiolytics dispensation

Sex 4.775 1 0.029 1.944 1.071-3.528

χ2=5.8;df=8;p=0.668 Nursing home 7.417 1 0.006 3.304 1.398-7.810

BDRS behavior 5.338 1 0.021 1.178 1.025-1.354

Hypnotics dispensation BDRS cognitive 4.250 1 0.039 1.514 1.021-2.247 χ2=10.0;df=8;p=0.267

SSRI dispensation

Sex 9.692 1 0.002 2.226 1.345-3.685

χ2=6.8;df=8;p=0.562 ADdep 14.754 1 <0.001 3.072 1.733-5.448

MMSE 6.458 1 0.011 1.074 1.017-1.135

All the models used as covariables: sex, age, education, civil status, residence, Mini Mental State Examination (MMSE), Blessed Dementia

Rating Scale (BDRS) cognitive, functional, and behavioral, Clinical Dementia Rating, anti-dementia drugs dispensation, and subtype of

dementia. ADdep: Alzheimer’s disease with depressed mood: ADdel: Alzheimer’s disease with delusions.

27  

Annex 1 – Drugs included in this study

Antipsychotics: haloperidol (N05AD01), clotiapine (N05AX09), levopromazine

(N05AA02), chlorpromazine (N05AA01), periciazine (N05AC01), zuclopentixol

(N05AF05), risperidone (N05AX08), quetiapine (N05AH04), amisulpride (N05AL01),

ziprasidone (N05AE04), olanzapine (N05AH03), aripiprazole (N05AX12), tiapride

(N05AL03), paliperidone (N05AX13), and pimozide (N05AG02). Lithium was also

included in this group, due to its ATC code classification as an antipsychotic

(N05AN01).

Selective serotonin reuptake inhibitors (SSRI): fluoxetine (N06AB03), citalopram

(N06AB04), paroxetine (N06AB05), sertraline (N06AB06), fluvoxamine (N06AB08),

and escitalopram (N06AB10).

Anxiolytics: diazepam (N05BA01, N05BA51), potassium clorazepate (N05BA05,

N05BA55), lorazepam (N05BA06), bromazepam (N05BA08), clobazam (N05BA09),

ketazolam (N05BA10), alprazolam (N05BA12), bentazepam (N05BA91), hydroxyzine

(N05BB01), buspirone (N05BE01), and passiflorine (N05BX92).

Hypnotics: flurazepam (N05CD01), flunitrazepam (N05CD03), triazolam (N05CD05),

lormetazepam (N05CD06), midazolam (N05CD08), quazepam (N05CD10), loprazolam

(N05CD11), zopiclone (N05CF01), zolpidem (N05CF02), and clometiazol (N05CM02).

Anti-dementia drugs: donepezil (N06DA02), rivastigmine (N06DA03), galantamine

(N06DA04), and memantine (N06DX01).