Scholarly article on topic 'High prevalence of psychotropic drug use among persons with and without Alzheimer׳s disease in Finnish nationwide cohort'

High prevalence of psychotropic drug use among persons with and without Alzheimer׳s disease in Finnish nationwide cohort Academic research paper on "Clinical medicine"

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{"Psychotropic drugs" / "Alzheimer׳s disease" / "Older persons"}

Abstract of research paper on Clinical medicine, author of scientific article — Heidi Taipale, Marjaana Koponen, Antti Tanskanen, Anna-Maija Tolppanen, Jari Tiihonen, et al.

Abstract Psychotropic drugs are used for treatment of behavioral and psychological symptoms of dementia (BPSD) although they are associated with serious adverse drug events. Objective of our study was to investigate prevalence of psychotropic drug use one year after diagnoses of Alzheimer׳s disease (AD), to compare prevalence to persons without AD and to assess changes in prevalence over time. Data from the MEDALZ (Medication use and Alzheimer׳s disease) cohort was utilized in the study including all 69,080 community-dwelling persons with new diagnosis of AD during years 2005–2011 in Finland. Four age-, gender- and region of residence-matched persons without AD were identified for each case. Register-based data included prescription drug purchases and comorbidities from Special Reimbursement Register. Annual prevalence of psychotropic drug use one year after diagnosis was determined for each person. Psychotropic drugs were used by 53% of persons with AD compared with 33% of persons without AD during one year after diagnoses. Persons with AD were six times more likely to use antipsychotics and three times more likely to use antidepressants whereas benzodiazepine and related drug (BZDR) use was comparable between persons with and without AD. According to year of AD diagnoses during 2005–2011, antipsychotic use increased from 18% to 20% (p<0.0001) and BZDR use declined from 31% to 26% (p<0.0001) among persons with AD. Widespread utilization of psychotropic drugs was observed among persons with AD. Despite safety warnings of antipsychotic use for BPSD, antipsychotic use increased from 2005 to 2011 among newly diagnosed persons with AD in Finland.

Academic research paper on topic "High prevalence of psychotropic drug use among persons with and without Alzheimer׳s disease in Finnish nationwide cohort"

European Neuropsychopharmacology (2014) 24, 1729-1737

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High prevalence of psychotropic drug use ^ among persons with and without Alzheimer's disease in Finnish nationwide cohort

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Heidi Taipalea,b,n, Marjaana Koponena,b, Antti Tanskanenc,d, Anna-Maija Tolppanenb,e, Jari Tiihonenc,f, Sirpa Hartikainena,b

aKuopio Research Centre of Geriatric Care, University of Eastern Finland, Kuopio, Finland bSchool of Pharmacy, University of Eastern Finland, Kuopio, Finland cDepartment of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden dNational Institute for Health and Welfare, Helsinki, Finland

eResearch Centre for Comparative Effectiveness and Patient Safety (RECEPS), University of Eastern Finland, Kuopio, Finland

fDepartment of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland

Received 3 June 2014; received in revised form 18 August 2014; accepted 11 October 2014

KEYWORDS

Psychotropic drugs; Alzheimer's disease; Older persons

Abstract

Psychotropic drugs are used for treatment of behavioral and psychological symptoms of dementia (BPSD) although they are associated with serious adverse drug events. Objective of our study was to investigate prevalence of psychotropic drug use one year after diagnoses of Alzheimer's disease (AD), to compare prevalence to persons without AD and to assess changes in prevalence over time. Data from the MEDALZ (Medication use and Alzheimer's disease) cohort was utilized in the study including all 69,080 community-dwelling persons with new diagnosis of AD during years 2005-2011 in Finland. Four age-, gender- and region of residence-matched persons without AD were identified for each case. Register-based data included prescription drug purchases and comorbidities from Special Reimbursement Register. Annual prevalence of psychotropic drug use one year after diagnosis was determined for each person. Psychotropic drugs were used by 53% of persons with AD compared with 33% of persons without AD during one year after diagnoses. Persons with AD were six times more likely to use antipsychotics and three times more likely to use antidepressants whereas benzodiazepine and related drug (BZDR) use was comparable between persons with and without AD. According to year of AD diagnoses during 2005-2011, antipsychotic use increased from 18% to 20% (p<0.0001) and BZDR use declined from 31% to 26% (p<0.0001) among persons with AD. Widespread utilization of psychotropic drugs was observed among persons with AD. Despite safety warnings of

*Corresponding author at: Kuopio Research Centre of Geriatric Care, University Of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland. Tel.: + 358443361265; fax: + 35817162424.

E-mail address: heidi.taipale@uef.fi (H. Taipale).

http://dx.doi.org/10.1016/j.euroneuro.2014.10.004

0924-977X/© 2014 Elsevier B.V. and ECNP. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

antipsychotic use for BPSD, antipsychotic use increased from 2005 to 2011 among newly diagnosed persons with AD in Finland.

© 2014 Elsevier B.V. and ECNP. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

1. Introduction

Psychotropic drugs are used in the treatment of behavioral and psychological symptoms of dementia (BPSD) in persons with Alzheimer's disease (AD) (Finnish Medical Society Duodecim, 2010). Antidementia drugs are recommended as the first-line treatment for BPSD. Treatment with psy-chotropic drugs is recommended only for most severe symptoms and for short-term use if non-pharmacological options are not effective.

Psychotropic drugs have been associated with serious adverse drug events among older persons and persons with dementia. Antipsychotics have been linked to an increased risk of stroke (Mittal et al., 2011). All psychotropic drugs have been associated with falls and hip fractures (Cumming and Le Couteur, 2003; Hartikainen et al., 2007; Coupland et al., 2011; Oderda et al., 2012; Xing et al., 2014). Studies regarding the risk of death associated with psychotropic drug use have been inconclusive. Numerous studies indicate the association between antipsychotic use and an increased mortality risk (Schneider et al., 2005; Wang et al., 2005; Schneeweiss et al., 2007; Ballard et al., 2009; Kales et al., 2012; Gerhard et al., 2014) with some conflicting results (Gardette et al., 2012; Lopez et al., 2013), whereas antidepressant (Ried et al., 2011; Coupland et al., 2011) and benzodiazepine studies (Kripke et al., 1998; Gisev et al., 2011) show mixed results. Antipsychotic and benzodiazepine use has been associated with decline in cognition (Hanlon et al., 1998; Byerly et al., 2001; Paterniti et al., 2002) which counteracts the main goals in the treatment of AD including preservation of cognitive function and delay of institutiona-lization (Finnish Medical Society Duodecim, 2010).

Few previous studies have investigated psychotropic drug use in persons with incident dementia. Martinez et al. (2013) determined prescribed prevalence of psychotropic drug use at the time of dementia diagnoses during 1995-2011. Schulze et al. (2013a) determined prevalence of antipsychotic use in the year of dementia incidence and studied the impact of safety warnings on prevalence of antipsychotic use (Schulze et al., 2013b). Franchi et al. (2012) investigated changes in antipsychotic use after the safety warnings among persons prescribed with acetylcholinesterase inhibitors. There is a lack of studies concerning prevalence of psychotropic drug use at the time of clinically verified diagnosis of Alzheimer's disease compared with matched comparison persons. Objective of our study was to investigate the prevalence of psychotropic drug use one year after diagnosis of Alzheimer's disease, to compare the prevalence with persons without AD and to assess changes in prevalence between persons diagnosed in 2005-2011.

2. Experimental procedures

Data from the MEDALZ (Medication use and Alzheimer's disease) cohort was utilized in the study. The MEDALZ cohort consists of all

73,005 persons diagnosed with AD between 2005 and 2011 in Finland. Four age-, gender- and region of residence-matched persons without AD were identified from database including all residents, leading to the cohort of 365,011 persons. Persons without AD were chosen based on not having diagnoses of AD or antidementia drug purchases at the index date (date of AD diagnosis for the case) or 12 months after that. Furthermore, non-AD person needed to be alive and not in long-term care facility during the month of AD diagnosis for the case. During the follow-up, some persons in non-AD group developed AD (N=14,343), and they were defined as AD cases and four comparison persons were identified as described.

Persons with AD were identified from the Special Reimbursement Register which includes data on entitlement to special reimbursement of drugs based on clinically diagnosed chronic diseases. Identification of AD cases and registers is described in more detail in Tolppanen et al. (2013). In short, the Finnish Current Care Guideline recommends that all persons with AD are treated with antidementia drugs unless there is a contraindication for the use (Finnish Medical Society Duodecim, 2010). Persons with probable AD need a verified diagnosis completed according to an exact diagnostic protocol monitored by the Social Insurance Institution to be entitled to reimbursed antidementia drugs. The verified AD diagnosis includes computed tomography or magnetic resonance imaging scan, and confirmation of the diagnosis by a neurologist or geriatrician. The special reimbursement for AD medication is not withdrawn when AD progresses to severe stage. Diagnosis of AD was based on the NINCDS-ADRDA (McKhann et al., 1984) and DSM-IV criteria (American Psychiatric Association, 1994).

Data of the MEDALZ cohort has been linked to several nationwide registers including Prescription Register (1995-2012), Special Reimbursement Register (1972-2012), Register of Care at Social Institutions (1995-2012), and Hospital Discharge Register (1972-2012). Prescription Register includes information on all purchases of prescribed and reimbursed drugs categorized according to Anatomical Therapeutic Chemical - classification system (ATC) (WHO, 2014). Data were de-identified before submission to the research team and thus, no ethics committee approval was required.

In this study, psychotropic drug purchases one year after index date (i.e. the date of AD diagnosis) were extracted (annual prevalence). The index date of the case was determined as starting date for 12 months follow-up period for comparison persons. Antipsychotics were defined as ATC class N05A excluding lithium. Atypical antipsychotics were defined as ziprasidone, clozapine, olanzapine, quetiapine, risperidone, aripiprazole, asenapine and paliperidone, and other drugs in N05A (excluding lithium) were classified as conventional antipsy-chotics (chlorpromazine, levomepromazine, dixyrazine, perphenazine, periciazine, thioridazine, haloperidol, melperone, sertindole, flupen-tixol, chlorprothixene, zuclopenthixol, pimozide, and sulpiride). Anti-depressants were defined as N06A and further categorized as tricyclic antidepressants (N06AA), selective serotonin reuptake inhibitors (SSRIs) (N06AB) and other antidepressants (N06AX). Benzodiazepines and related drugs (BZDRs) were defined as N05BA, N05CD and N05CF. BZDRs were further classified as benzodiazepines (BZDs) (N05BA and N05CD) and Z-drugs (N05CF). Most commonly purchased drug substances were calculated for each psychotropic drug class and separately among persons with and without AD. One person may have purchased several drugs during the follow-up and thus, contributed to several substances.

For the present study, persons were excluded if they were in long-term care for over 240 days of the year after AD diagnosis

because drugs used in long-term care are not available in the Prescription Register. Persons with dementia related to Parkinson's disease are also granted special reimbursement for antidementia drugs. These persons were excluded from the present study. Exclusions are described in more detail in Figure 1.

2.1. Statistical analysis

Descriptive statistical analyses were undertaken using means, standard deviations (SD) and percentages. All analyses included annual prevalence data one year after the index date. Prevalence between cases and controls was compared with logistic regression with odds ratios (ORs) and 95% confidence intervals (CIs). Prevalence of psychotropic drug use between persons diagnosed in different years was compared with logistic regression to prevalence of those diagnosed in 2005. Trend in prevalence in 2005-2011 was modelled as year being a continuous variable and tested with Cochran-Armitage Trend test. Age was measured at the index date. Use of two or more psychotropic drugs was defined as use of antipsychotics, antidepressants and BZDRs. All analyses were performed using SAS (version 9.3; SAS Institute Inc., Cary, NC, USA).

3. Results

The study population consisted of 69,080 persons with AD and 275,021 persons without AD. Mean age of persons with and without AD was 80 years (SD 7.1 years), and 65% were female.

During one year after AD diagnoses, 53% of persons with AD purchased at least one psychotropic drug. Antipsychotics were utilized by 20%, antidepressants by 28% and BZDRs by 29% of persons with AD (Table 1). At least two psychotropic drugs were purchased by 20% of persons with AD.

During the one year follow-up time, 33% of persons without AD purchased at least one psychotropic drug and 8% had purchased at least two psychotropics. Antipsychotics were used by 4%, antidepressants by 11% and BZDRs by 27% of persons without AD (Table 1).

Persons with AD used all psychotropic drug classes more frequently than persons without AD (Table 2). Persons with

AD were six times more likely to use antipsychotics and three times more likely to use antidepressants than persons without AD. More frequent utilization of psychotropic drugs was observed among genders and in all age groups. Only exception was BZDR use among persons aged > 85 years with whom no difference was found between persons with and without AD.

Antipsychotic use slightly increased from 2005 to 2011 when prevalence was compared between years of AD diagnoses in persons with AD (Figure 2). In contrast to antipsychotic use,

Table 1 Annual prevalence of psychotropic drug use during one year after diagnoses of AD in MEDALZ data.

Drug group Persons Persons

with AD without AD

N = 69,080 N = 275,021

Users % (N) Users % (N)

Antipsychotics 20% 4% (10,492)

(13,628)

Conventional 2.5% (1740) 1.4% (3714)

antipsychotics

Atypical antipsychotics 18.2% 2.8% (7555)

(12,588)

Antidepressants 28% 11% (31,416)

(19,296)

Tricyclic antidepressants 0.9% (617) 1.5% (4101)

SSRIs 17.9% 6.1% (16,815)

(12,392)

Other antidepressants 11.9% 5.0% (13,790)

(8198)

Benzodiazepines and 29% 27% (73,740)

related drugs (20,251)

Benzodiazepines 16.9% 13.1% (35,964)

(11,690)

Z-drugs 15.7% 16.3% (44,737)

(10,857)

to Parkinson's disease and long-term care in the MEDALZ data.

Figure 1 Flow chart of exclusions based on dementia related

Table 2 Comparison of psychotropic drug use among persons with and without AD in MEDALZ data.

Drug Persons with AD N = 69,080 Persons without Odds ratio (95% CI)

AD N = 275,021

Antipsychotic use 20% (13,628) 4% (10,492) 6.20 (6.03-6.37)

Men 18%(4396) 3% (2954) 7.03 (6.69-7.38)

Women 21% (9232) 4% (7538) 5.88 (5.69-6.07)

<65 years 21% (480) 3% (308) 7.66 (6.58-8.92)

65-74 years 19% (2359) 3% (1446) 7.87 (7.35-8.43)

75-84 years 19% (7270) 4% (5363) 6.44 (6.20-6.68)

> 85 years 22% (3519) 5% (3375) 4.97 (4.72-5.22)

Antidepressant use 28% (19,296) 11% (31,416) 3.01 (2.95-3.07)

Men 22% (5300) 8% (7765) 3.20 (3.08-3.33)

Women 31% (13,996) 13% (23,651) 2.97 (2.90-3.04)

< 65 years 33% (748) 11% (954) 4.21 (3.77-4.70)

65-74 years 29% (3503) 9% (4405) 4.07 (3.87-4.28)

75-84 years 28% (10,525) 11% (17,025) 3.02 (2.94-3.11)

> 85 years 28% (4520) 14% (9032) 2.35 (2.25-2.44)

Benzodiazepine and related drug use 29% (20,251) 27% (73,740) 1.13 (1.11-1.15)

Men 26% (6260) 21% (19,823) 1.35 (1.31-1.39)

Women 31% (13,991) 30% (53,917) 1.05 (1.03-1.07)

< 65 years 22% (498) 13% (1208) 1.84 (1.64-2.06)

65-74 years 25% (3021) 19% (9369) 1.39 (1.33-1.46)

75-84 years 30% (11,285) 27% (41,729) 1.10 (1.08-1.14)

> 85 years 33% (5447) 33% (21,434) 1.00 (0.97-1.04)

BZDR use declined and antidepressant use remained stable. Among persons without AD, prevalence of antipsychotic and antidepressant use remained stable whereas BZDR use increased during 2005-2008 and then declined to somewhat lower level than observed in 2005. Antipsychotic use increased according to year of diagnoses in 2008-2011 by 10-20% compared to those diagnosed in 2005 (Table 3). In 2008, antipsy-chotic use started to increase whereas BZDR use started to decline compared to those diagnosed in 2005. Among persons without AD, antipsychotic use declined and antidepressant use slightly increased in 2006-2011 compared to year 2005. In both persons with and without AD, SSRI use declined whereas use of other antidepressants increased during the follow-up. Similarly in both groups, conventional antipsychotic use declined and atypical antipsychotic use increased.

The most frequently purchased antipsychotics among persons with and without AD were risperidone and quetia-pine (Table 4). Among antidepressants, most commonly purchased drugs were mirtazapine, citalopram and escita-lopram among groups. Among persons without AD, amitrip-tyline was more commonly used antidepressant compared to persons with AD. Most frequently used BZDRs were zopi-clone, temazepam and oxazepam among groups. Lorazepam was ranked as the fourth most common BZDR among persons with AD whereas zopiclone among persons without AD. In addition, the prevalence of diazepam use was higher among persons without AD compared to persons with AD.

Among psychotropic drug prescribers, non-specialized physicians accounted for 48-60% of the first prescriptions of psychotropic drug classes. The prescriptions stated by specialized physicians were further analyzed according to prescribers' specialty. Among persons with AD, general practitioners were the most common prescribers (41% of antipsychotic, 41% of antidepressant and 57% of BZDR

prescriptions). Geriatricians followed the GPs representing 26% of antipsychotic, 26% of antidepressant and 15% of BZDR prescriptions. Third ranked prescriber specialty was neurologists (14% of antipsychotic, 14% of antidepressant and 6% of BZDR prescriptions) whereas psychiatrist was the fourth most common prescribers (7% of antipsychotics, 5% of antidepressants and 5% of BZDRs). The prescriber rankings were similar among persons without AD except that percentage of general practitioners was higher (varied from 56% of antipsychotics to 65% of BZDRs) and psychiatrists were ranked the second most common prescribers of antipsychotics (18%).

4. Discussion

In our study, psychotropic drugs were more frequently used by persons with AD compared to persons without AD. Over half of persons with AD used at least one psychotropic drug during one year after diagnosis and they were six times more likely to use antipsychotics and three times more likely to use antidepressants compared to persons without AD. According to year of AD diagnosis during 2005-2011, we found an increasing trend of antipsychotic use whereas BZDR use declined among persons with AD.

We found higher prevalence of antipsychotic use (20%) one year after AD diagnoses compared to a previous study (13%) that included persons with all types of dementia diagnoses (Martinez et al., 2013). One study reported higher prevalence (25%) of antipsychotic drug use among persons with dementia during one year after diagnoses but they included also persons living in institutional care (Schulze et al., 2013a). In their study, prevalence of antipsychotic use was 11% among community-dwelling persons without need for long-term care services. Thus, prevalence of

Figure 2 Changes in prevalence of psychotropic drug use according to year of AD diagnoses. (A) antipsychotics, (B) benzodiazepines and related drugs, (C) conventional antipsychotics, (D) benzodiazepines, (E) atypical antipsychotics, (F) Z-drugs, (G) antidepressants, (H) tricyclic antidepressants, (I) SSRIs, and (J) other antidepressants.

Table 3 Prevalence of psychotropic drug use during one year after diagnoses of Alzheimer's disease according to diagnoses year in persons with Alzheimer's disease.

Prevalence

2006 OR (95% CI) 2007 OR (95% CI) 2008 OR (95% CI) 2009 OR (95% CI) 2010 OR (95% CI) 2011 OR (95% CI) p-Value for trenda

Antipsychotic use 1.01 (0.94-1.09) 1.06

Typicals 1.00 (0.85-1.18) 0.75

Atypicals 1.01 (0.93-1.09) 1.12

Antidepressant use 1.01 (0.94-1.08) 1.04

Tricyclics 0.86 (0.64-1.15) 0.74

SSRIs 0.94 (0.87-1.02) 0.99

Other antidepressants 1.16 (1.05-1.30) 1.19

Benzodiazepine and related drug use 1.01 (0.95-1.08) 0.96

Benzodiazepines 1.03 (0.95-1.11) 0.94

Z-drugs 1.00 (0.92-1.08) 0.98

Persons without AD

Antipsychotic use 0.85 (0.78-0.92) 0.88

Typicals 0.80 (0.71-0.89) 0.73

Atypicals 0.88 (0.80-0.97) 1.00

Antidepressant use 1.05 (1.00-1.11) 1.04

Tricyclics 1.04 (0.92-1.17) 0.96

SSRIs 1.04 (0.98-1.11) 0.97

Other antidepressants 1.08 (0.99-1.16) 1.20

Benzodiazepine and related drug use 1.06 (1.02-1.10) 1.05

Benzodiazepines 1.03 (0.99-1.08) 0.98

Z-drugs 1.09 (1.04-1.14) 1.12

0.98 0.63 1.03 0.98 0.550.92 1.070.90 0.87 0.91

0.82 0.65 0.91 0.990.85 0.92 1.11 1.02 0.941.08

1.14) 0.89) 1.21) 1.12) 0.99) 1.06) 1.31) 1.03) 1.01) 1.06)

0.95) 0.82) 1.10) 1.09) 1.08) 1.03) 1.29) 1.09) 1.02) 1.17)

1.12 0.70 1.20 1.06 0.75 0.95

1.29 0.93 0.88 0.99

0.89 0.59 1.10 1.05 0.94 0.94

1.30 1.11 0.95 1.27

1.040.591.110.990.560.881.170.880.810.91-

1.21) 0.83) 1.30) 1.13) 1.00) 1.02) 1.42) 0.99) 0.94) 1.07)

0.83-0.96) 0.53-0.67) 1.01-1.21) 1.01-1.10) 0.83-1.05) 0.89-1.00)

1.21-1.40) 1.08-1.15) 0.91-0.99)

1.22-1.32)

1.14 0.68 1.22 1.04 0.70 0.88 1.42 0.89 0.83 0.95

0.88 0.53 1.13 1.06 0.85 0.88 1.50 1.10 0.88 1.31

1.06 0.57 1.13 0.97 0.52 0.82 1.29 0.83 0.77 0.88

0.82 0.47 1.03 1.01 0.75 0.83 1.38 1.06 0.84 1.26

1.23) 0.81) 1.32) 1.11) 0.93) 0.95) 1.56) 0.94) 0.90) 1.03)

0.95) 0.60)

1.24) 1.11) 0.95) 0.94) 1.59) 1.14) 0.92) 1.37)

1.19 0.64 1.30 1.04 0.74 0.85 1.50 0.87 0.77 0.97

0.86 0.51 1.11 1.11 0.85 0.89 1.64 1.04 0.81 1.27

1.10 0.53 1.20 0.97 0.56 0.79 1.37 0.81 0.71 0.89

1.27) 0.76) 1.40) 1.10) 0.99) 0.92) 1.65) 0.92) 0.83) 1.05)

0.79-0.92) 0.45-0.57) 1.02-1.22) 1.06-1.16) 0.75-0.96) 0.84-0.94) 1.53-1.76) 1.01-1.07) 0.77-0.84) 1.22-1.32)

1.09 0.43 1.22 1.02 0.66 0.80 1.57 0.76 0.71 0.85

0.92 0.47 1.26 1.11 0.89 0.87 1.67 0.97 0.76 1.21

1.010.361.140.960.490.741.440.720.660.790.860.411.161.060.790.821.560.940.731.16-

1.17) 0.52) 1.32) 1.09) 0.88) 0.86) 1.72) 0.81) 0.76) 0.92)

0.99) 0.52) 1.37) 1.16) 0.99) 0.92) 1.79) 1.01) 0.79) 1.26)

<0.0001 <0.0001 <0.0001 0.5070 0.0037 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001

0.1458 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 0.0285 <0.0001 <0.0001

Prevalences are compared to prevalence of those diagnosed in 2005. Logistic regression, unadjusted. ap-Value for trend, Cochran-Armitage Trend test, year of diagnoses as continuous variable, 2-sided.

Table 4 Most commonly purchased psychotropic drug substances in the MEDALZ cohort one year after diagnoses among persons with and without Alzheimer's disease (AD).

Drug Persons with AD Persons without AD

N=69,080 N=275,021

N (%) N (%)

Antipsychotics

Risperidone 7738 (11.20) 3730 (1.36)

Quetiapine 4936 (7.15) 3045 (1.11)

Olanzapine 806 (1.17) 912 (0.33)

Haloperidol 712 (1.03) 704 (0.26)

Antidepressants

Mirtazapine 6689 (9.68) 10,564 (3.84)

Citalopram 6636 (9.61) 9856 (3.58)

Escitalopram 4942 (7.15) 4853 (1.76)

Venlafaxine 828 (1.20) 1318 (0.48)

Duloxetine 673 (0.97) 1265 (0.46)

Sertralin 643 (0.93) 1015 (0.37)

Amitriptyline 350 (0.51) 2325 (0.85)

Benzodiazepines and related drugs

Zopiclone 9587 (13.88) 38,145 (13.87)

Temazepam 5006 (7.25) 16,778 (6.10)

Oxazepam 4703 (6.81) 11,135 (4.05)

Lorazepam 1758 (2.54) 2944 (1.07)

Zopiclone 1459 (2.11) 7252 (2.64)

Diazepam 894 (1.29) 4321 (1.57)

antipsychotic use among Finnish community-dwelling persons diagnosed with AD was higher than reported in previ ous studies from the UK and Germany. This may indicate treatment practices favoring antipsychotic use although the Finnish clinical care guideline on AD recommends antipsy-chotic use only for severe BPSD symptoms (Finnish Medical Society Duodecim, 2010).

We also found higher antidepressant consumption (28%) among persons with AD than Martinez et al. (2013) (22%). However, they found an increasing trend of antidepressant use in those diagnosed in 1995-2011 and prevalence in 2011 (26%) was almost similar to our findings. We did not find changes in antidepressant use during the years 2005-2011 except decreasing use of tricyclics and SSRIs and corresponding increase in use of "other antidepressants" like mirtazapine. Other previous studies (Guthrie et al., 2010; Rhee et al., 2011; Rattinger et al., 2013) have reported antidepressant use in samples including persons with differing times since diagnoses and thus, are not directly comparable to our study including newly diagnosed persons with AD.

BZDRs were the most commonly used psychotropic drugs in our study with prevalence of 29% among persons with AD. We also found almost similar prevalence (27%) among persons without AD. Prevalence among persons with AD in our study is much higher than reported by previous studies in which 10% used hypnotics and 5% used anxiolytics (Martinez et al., 2013). The frequent utilization of BZDRs among persons with and without AD is concerning because these drugs are associated with cognitive decline (Hanlon et al., 1998; Paterniti et al., 2002) and an increased risk of

falls among older persons (Cumming and Le Couteur, 2003; Hartikainen et al., 2007). However, decline in prevalence of BZDR use in 2005-2011 was an encouraging finding and may imply more careful prescribing among persons with AD. Among persons without AD, prevalence of BZDR use increased until 2009 and then declined to the level than observed in 2005. Further studies are needed to verify if this declining trend was remained after 2011.

Antipsychotic use was six times more common and antidepressant use three times more common among persons with AD compared to persons without AD in our study. Thus, our figures are similar to a previous study of anti-psychotic use in persons with dementia compared to those without (Schulze et al., 2013a, 2013b). We found more frequent utilization of atypical antipsychotics whereas Schulze and coworkers reported that conventional antipsy-chotics were more commonly used. In our study, conventional antipsychotic use declined and atypical antipsychotic use increased according to year of AD diagnoses in 20052011. Both conventional and atypical antipsychotics are associated with an increased risk of stroke (Mittal et al., 2011) but conventional antipsychotics are more likely to cause serious adverse drug effects including anticholinergic effects and parkinsonism (Byerly et al., 2001).

Antipsychotic use has also been associated with an increased risk of death among older persons with and without dementia (Schneider et al., 2005; Wang et al., 2005; Schneeweiss et al., 2007; Ballard et al., 2009; Kales et al., 2012; Gerhard et al., 2014). The risk has been associated with both conventional and atypical antipsychotics but some studies indicate higher risk for conventional antipsychotics compared with atypicals (Wang et al., 2005; Gill et al., 2007; Schneeweiss et al., 2007; Kales et al., 2012; Gerhard et al., 2014). There may be differences between mortality risks associated with different drug substances (Kales et al., 2012; Gerhard et al., 2014) and there is some evidence of the dose-response relationship on the risk of death (Gerhard et al., 2014). The risk is pronounced especially at the initiation of treatment (until 180 days) (Wang et al., 2005; Gill et al., 2007; Schneeweiss et al., 2007; Kales et al., 2012; Gerhard et al., 2014). Sustained risk in long-term use has been reported in some studies (Ballard et al., 2009) whereas other studies have not verified the risk in long-term use (Gardette et al., 2012; Lopez et al., 2013). However, the assessment of long-term effects is more challenging in terms of study design. More studies with vigorous study design, control of potential confounders, and with appropriate sample size to ensure statistical power are needed. However, the risk-benefit ratio should be carefully evaluated based on the current knowledge before starting antipsychotic drug use among vulnerable persons with dementia.

In our study, antipsychotic use increased according to year of AD diagnoses in 2005-2011. International warnings of serious adverse drug events associated with antipsychotic use in the treatment of BPSD were announced in 2005 and 2008 (FDA, 2005, 2008; EMA—European Medicines Agency, 2008). In our study, antipsychotic use remained stable in 2006-2007 compared to year 2005 but started to increase in 2008. This in contrast to previous findings in which declining use of antipsychotics was reported among those diagnosed in 1995-2011 (Martinez et al., 2013) and modest decline after the safety warnings (Franchi et al., 2012). However,

although Schulze et al. (2013b) found declining prevalence of antipsychotic use in 2004-2009 at the same time the defined daily dose per treated patient increased. Reasons for increasing antipsychotic use in Finland despite safety warnings should be further investigated. Reasons may be related to the lack of information on safety warnings, difficulties to change treatment traditions or lack of alternatives for antipsychotics in treatment guidelines and recommendations stated by the authorities.

As antipsychotic use increased, we found decline in benzodiazepine and related drug use in 2005-2011 among persons with AD. Declining BZDR use may indicate more careful consideration of risks and benefits among persons with AD. It is possible that adverse events associated with BZDRs, such as an increased risk of falls and daytime sedation, are more likely to be observed in clinical practice than adverse events associated with antipsychotic use. However, the overall level of BZDR use in our study was significantly higher than in the previous studies (Guthrie et al., 2010; Rhee et al., 2011; Martinez et al., 2013).

Psychotropic drugs were most commonly prescribed by physician without specialty. In Finland, diagnoses of AD involve geriatricians and neurologists but treatment after diagnoses continues in general healthcare where physicians without specialty represent the main proportion of prescri-bers together with general practitioners.

Our nationwide cohort included all persons with new clinically diagnosed AD in 2005-2011 and thus, our results represent treatment practice among community-dwelling persons in Finland. Further, we compared psychotropic drug use of persons with AD to age-, gender- and region of residence matched persons without AD. Drug data was obtained from Prescription Register which represents actual drug purchases instead of prescribed drugs and register-based data is not object to recall or reporting bias compared to self-reported data. Only reimbursed drug purchases are recorded in the Prescription Register and some small packages of BZDRs are not reimbursed. This limitation is likely to underestimate exposure to BZDR drugs. Indications for psychotropic drug use and severity of AD were not included in our data which are limitations in our study.

In conclusion, we found widespread utilization of psycho-tropic drugs among persons with AD. All psychotropic drug classes were more frequently used by persons with AD although prevalence of use among comparison persons without AD was also significant. The safety warnings related to antipsychotic use among persons with dementia have not been effective as we found an increasing trend of antipsychotic use among those diagnosed in 2006-2011. High prevalence of antipsychotic and BZDR use one year after AD diagnoses is concerning as both have been associated with cognitive decline. The main goals in the treatment of AD include preservation of cognitive function and delay of institutionalization by maintaining functioning in the activities of daily living (Finnish Medical Society Duodecim, 2010). Anti-dementia drugs are recommended for persons with AD unless there is a contraindication for use. Initiation of antidementia drug use takes place at the time of diagnoses and thus, the follow-up time in our study represents also the initiation and titration period of anti-dementia drugs. Thus, frequent use of drugs associated with cognitive decline counteracts the preservation of cognitive function and maintenance of functioning in activities of daily living.

Role of funding source

No grants were received for this study.

Contributors

All authors were involved in designing the study. HT performed the data analysis and wrote the first draft of the manuscript. All authors interpreted data, critically revised the manuscript, read and approved the final manuscript.

Conflict of interest

JT has served as a consultant to Lundbeck, Organon, Janssen-Cilag, Eli Lilly, AstraZeneca, F. Hoffman-La Roche, and Bristol-Myers Squibb. He has received fees for giving expert opinions to Bristol-Myers Squibb and GlaxoSmithKline, lecture fees from Janssen-Cilag, Bristol-Myers Squibb, Eli Lilly, Pfizer, Lundbeck, GlaxoSmithKline, AstraZeneca and Novartis; and Grant from Stanley Foundation, Grant 12T-010.JT is a member of advisory board in AstraZeneca, Janssen-Cilag, and Otsuka. Other authors declare no conflicts of interest.

Acknowledgments

None to declare.

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