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Pharmacological treatments for neuropsychiatric symptoms of dementia in long-term care: a systematic review

Published online by Cambridge University Press:  19 October 2012

Dallas P. Seitz*
Affiliation:
Department of Psychiatry, Queen's University, Kingston, Ontario, Canada
Sudeep S. Gill
Affiliation:
Division of Geriatric Medicine, Queen's University, Kingston, Ontario, Canada
Nathan Herrmann
Affiliation:
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
Sarah Brisbin
Affiliation:
Department of Psychiatry, Queen's University, Kingston, Ontario, Canada
Mark J. Rapoport
Affiliation:
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada Department of Psychiatry, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
Jenna Rines
Affiliation:
Department of Psychiatry, Queen's University, Kingston, Ontario, Canada
Kimberley Wilson
Affiliation:
Canadian Coalition for Seniors’ Mental Health, Toronto, Ontario, Canada
Ken Le Clair
Affiliation:
Department of Psychiatry, Queen's University, Kingston, Ontario, Canada
David K. Conn
Affiliation:
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada Department of Psychiatry, Baycrest Centre, Toronto, Ontario, Canada
*
Correspondence should be addressed to: Dr. Dallas Seitz, Geriatric Psychiatry Services, Providence Care – Mental Health Services, 752 King Street West, Kingston, Ontario, Canada, K7L 4X3. Telephone: 613-548-5567, ext: 5942; Fax: 613-540-6128. Email: seitzd@providencecare.ca
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Abstract

Background: Medications are frequently prescribed for neuropsychiatric symptoms (NPS) associated with dementia, although information on the efficacy and safety of medications for NPS specifically in long-term care (LTC) settings is limited. The objective of this study was to provide a current review of the efficacy and safety of pharmacological treatments for NPS in LTC.

Methods: We searched MEDLINE, EMBASE, PsychINFO, and the Cochrane Library for randomized controlled trials comparing medications with either placebo or other interventions in LTC. Study quality was described using the Cochrane collaboration risk of bias tool. The efficacy of medications was evaluated using NPS symptom rating scales. Safety was evaluated through rates of trial withdrawals, trial withdrawals due to adverse events, and mortality.

Results: A total of 29 studies met inclusion criteria. The most common medications evaluated in studies were atypical antipsychotics (N = 15), typical antipsychotics (N = 7), anticonvulsants (N = 4), and cholinesterase inhibitors (N = 3). Statistically significant improvements in NPS were noted in some studies evaluating risperidone, olanzapine, and single studies of aripiprazole, carbamazepine, estrogen, cyproterone, propranolol, and prazosin. Study quality was difficult to rate in many cases due to incomplete reporting of details. Some studies reported higher rates of trial withdrawals, adverse events, and mortality associated with medications.

Conclusions: We conclude that there is limited evidence to support the use of some atypical antipsychotics and other medications for NPS in LTC populations. However, the generally modest efficacy and risks of adverse events highlight the need for the development of safe and effective pharmacological and non-pharmacological interventions for this population.

Type
Review Article
Creative Commons
Creative Common License - CCCreative Common License - BYCreative Common License - NCCreative Common License - SA
The online version of this article is published within an Open Access environment subject to the conditions of the Creative Commons Attribution-NonCommercial-ShareAlike licence . The written permission of Cambridge University Press must be obtained for commercial re-use.
Copyright
Copyright © International Psychogeriatric Association 2012

Introduction

Neuropsychiatric symptoms (NPS) associated with dementia are common in long-term care (LTC) settings with approximately 80% of individuals with dementia in LTC exhibiting NPS at any time (Zuidema et al., Reference Zuidema, Koopmans and Verhey2007; Seitz et al., Reference Seitz, Purandare and Conn2010). Guidelines (Canadian Coalition for Seniors’ Mental Health, 2006; Herrmann et al., Reference Herrmann, Gauthier and Lysy2007) and previous reviews (Sink et al., Reference Sink, Holden and Yaffe2005) have emphasized the importance of comprehensive assessment to rule out pain (Cohen-Mansfield and Mintzer, Reference Cohen-Mansfield and Mintzer2005; Sink et al., Reference Sink, Holden and Yaffe2005), delirium (Sink et al., Reference Sink, Holden and Yaffe2005), and environmental or interpersonal factors (Sink et al., Reference Sink, Holden and Yaffe2005) which may precipitate behaviors. Non-pharmacological interventions are usually recommended as first-line treatments for NPS. Unfortunately, knowledge of psychosocial interventions in LTC is low (Cohen-Mansfield and Jensen, Reference Cohen-Mansfield and Jensen2008), access to services for these interventions is limited (Conn, Reference Conn1992; Burns et al., Reference Burns, Wagner, Taube, Magaziner, Permutt and Landerman1993; Meeks, Reference Meeks1996; Reichman et al., Reference Reichman1998; Seitz et al., Reference Seitz, Adenuri, Gill, Gruneir, Herrmann and Rochon2011), their effectiveness may be modest (Seitz et al., Reference Seitz2012), and patients may not cooperate with these interventions (Cohen-Mansfield et al., Reference Cohen-Mansfield, Thein, Marx and Dakheel-Ali2012). Therefore, there remains a potential role for medications in managing NPS in LTC.

Psychotropic medications are frequently prescribed in LTC (Gruber-Baldini et al., Reference Gruber-Baldini, Boustani, Sloane and Zimmerman2004; Pitkala et al., Reference Pitkala, Laurila, Strandberg and Tilvis2004; Selbaek et al., Reference Selbaek, Kirkevold and Engedal2007). The estimated prevalence of the use of these medications among LTC residents with dementia is 25%–40% for antipsychotics (Pitkala et al., Reference Pitkala, Laurila, Strandberg and Tilvis2004; Rochon et al., Reference Rochon2007; Selbaek et al., Reference Selbaek, Kirkevold and Engedal2008; Nijk et al., Reference Nijk, Zuidema and Koopmans2009; Larrayadieu et al., Reference Larrayadieu2011; Snowdon et al., Reference Snowdon, Galanos and Vaswani2011), 25%–30% for antidepressants (Pitkala et al., Reference Pitkala, Laurila, Strandberg and Tilvis2004; Nijk et al., Reference Nijk, Zuidema and Koopmans2009; Snowdon et al., Reference Snowdon, Galanos and Vaswani2011), cognitive enhancers in 25%–30% (Seitz et al., Reference Seitz, Gruneir, Conn and Rochon2009), and benzodiazepines in 15%–30% (Pitkala et al., Reference Pitkala, Laurila, Strandberg and Tilvis2004; Selbaek et al., Reference Selbaek, Kirkevold and Engedal2008; Nijk et al., Reference Nijk, Zuidema and Koopmans2009; Snowdon et al., Reference Snowdon, Galanos and Vaswani2011). Systematic reviews and meta-analyses have indicated that some typical antipsychotics (Schneider et al., Reference Schneider, Pollock and Lyness1990; Lanctot et al., Reference Lanctot1998), atypical antipsychotics (Ballard and Waite, Reference Ballard and Waite2006; Schneider et al., Reference Schneider2006b), and antidepressants (Seitz et al., Reference Seitz, Adenuri, Gill, Gruneir, Herrmann and Rochon2011) may have benefits in treating certain NPS, although the magnitude of benefit may be limited and potentially outweighed by adverse events. Atypical antipsychotics, the most extensively studied and utilized medications for NPS, are also associated with serious adverse events such as death (Schneider et al., Reference Schneider, Dagerman and Insel2005; Wang et al., Reference Wang2005; Gill et al., Reference Gill2007) or stroke (Herrmann et al., Reference Herrmann, Mamdani and Lanctot2004, Gill et al., Reference Gill2005), as well as falls (Hien Le et al., Reference Hien Le2005), sedation (Schneider et al., Reference Schneider, Dagerman and Insel2006a), and cognitive decline (Schneider et al., Reference Schneider, Dagerman and Insel2006a; Vigen et al., Reference Vigen2011). Although there has been a decline in the use of antipsychotics with dementia recently, these medications continue to be used frequently (Kales et al., Reference Kales2011). The safety of other medications used to treat NPS in LTC has also been questioned (Huybrechts et al., Reference Huybrechts, Rothman, Silliman, Brookhart and Schneeweiss2011).

Although there are previous reviews on the use of psychotropic medications for the management of NPS (Schneider et al., Reference Schneider, Pollock and Lyness1990; Reference Schneider2006a; Borson and Raskind, Reference Borson and Raskind1997; Lanctot et al., Reference Lanctot1998; Sutor et al., Reference Sutor, Rummans and Smith2001; Kindermann et al., Reference Kindermann, Dolder, Bailey, Katz and Jeste2002; Snowden et al., Reference Snowden, Sato and Roy-Byrne2003; Alexopoulos et al., Reference Alexopoulos, Jeste, Chung, Carpenter, Ross and Docherty2005; Bharani and Snowden, Reference Bharani and Snowden2005; Sink et al., Reference Sink, Holden and Yaffe2005; Ballard and Howard, Reference Ballard and Howard2006; Kozman et al., Reference Kozman, Wattis and Curran2006; Herrmann and Lanctot, Reference Herrmann and Lanctot2007; Konavalov et al., Reference Konavalov, Muralee and Tampi2007; Saddichha and Pandey, Reference Saddichha and Pandey2008; Ballard et al., Reference Ballard, Corbett, Chitramohan and Aarsland2009a; Reference Ballard2009b; Conn and Seitz, Reference Conn and Seitz2010; Gauthier et al., Reference Gauthier, Cummings, Ballard, Brodaty, Grossberg, Robert and Lyketsos2010), few have focused exclusively on studies conducted in LTC settings (Snowden et al., Reference Snowden, Sato and Roy-Byrne2003; Bharani and Snowden, Reference Bharani and Snowden2005). Residents of LTC facilities with dementia may be particularly susceptible to adverse events associated with psychotropics when compared with community or hospital-based populations. Controlled trials and observational studies of older adults with dementia have indicated that LTC residents have more advanced age, more severe cognitive impairment, higher rates of comorbidity (Schneider et al., Reference Schneider, Dagerman and Insel2006a; Gill et al., Reference Gill2007; Rochon, Reference Rochon2008), and receive lower quality of routine and preventative care (Fahey et al., Reference Fahey, Montgomery, Barnes and Protheroe2003) than outpatient or hospital populations. In addition, higher rates of mortality have been observed for LTC residents with dementia newly started on antipsychotics when compared with community-dwelling populations (Gill et al., Reference Gill2007; Rochon et al., Reference Rochon2008). For these reasons, LTC residents may be particularly susceptible to mortality and other adverse events associated with psychotropic use which may have been underestimated in previous reviews which included both LTC and other populations within the same review. Also, some reviews have included both randomized and non-randomized studies (Bharani and Snowden, Reference Bharani and Snowden2005). Importantly, only a few previous reviews have assessed the quality of studies (Schneider et al., Reference Schneider, Dagerman and Insel2006a). Therefore, the objectives of this study were to provide a systematic review of randomized controlled trials (RCTs) for pharmacological treatments of NPS conducted specifically in LTC settings and evaluate the efficacy, and safety of treatments as well as the quality of studies.

Methods

Search strategy

Standard guidelines for conducting systematic reviews were used to guide the review process (Moher et al., Reference Moher, Liberati, Tetzlaff and Altman2009). We searched the electronic databases Medline, EMBASE, and PsychINFO (January 1980–February 2011), and the Cochrane Library using free text and medical subject headings to identify relevant articles (see Box 1, available as supplementary material attached to the electronic version of this paper at www.journals.cambridge.org/jid_IPG). Google Scholar was also searched for additional articles using key words and citation lists. Hand-searches of reference lists of retrieved articles, previous reviews, and guidelines (Canadian Coalition for Seniors’ Mental Health, 2006) were used to supplement the electronic database search.

Study selection

The titles and abstracts of citations from electronic databases were independently reviewed by two study authors. Full-text articles were then reviewed for inclusion criteria. Randomized, parallel-group, controlled trials comparing any pharmacological intervention to placebo, another medication, or non-pharmacological interventions were included. We only included studies where NPS was the primary study outcome. We included studies reporting overall levels of NPS using composite measures of NPS on commonly utilized rating scales (e.g. Neuropsychiatric Inventory) or on specific measures of agitation, psychosis, or aggression. Studies that only evaluated depression or apathy in LTC residents with dementia were excluded. We excluded uncontrolled pre–post studies and crossover designs given the high-placebo response rate observed in some studies (Schneider et al., Reference Schneider, Dagerman and Insel2006a). Study populations had to be exclusively from LTC or where LTC residents formed the majority (>50%) of participants. All English-language publications that provided sufficient detail for data extraction were included. Full-text articles were reviewed for inclusion criteria by two study authors with discrepancies resolved through discussion.

Data extraction

We extracted the following information from studies: dose of medication, number of participants, gender distribution, number and location of LTC facilities, dementia severity, method for diagnosing dementia, and study duration. We categorized studies according to pharmacological class. Baseline severity of NPS and change in NPS as reported on NPS rating scales (e.g. Cohen-Mansfield Agitation Inventory) were recorded. For dichotomous outcomes (e.g. number of individuals with a treatment response), the number of individuals with the outcome was recorded. For studies that did not report a primary outcome, we selected the change in NPS symptom rating scale total score as measured at study endpoint as the primary measure of efficacy. Safety and tolerability outcomes included: rates of trial withdrawals due to any cause, trial withdrawals due to adverse events, and mortality. All data were extracted in duplicate by two study authors using a standard data extraction form and discrepancies were resolved through further discussion.

Study quality

The Cochrane collaboration risk of bias assessment tool was utilized to describe the potential risk of bias associated with various aspects of study design (Higgins and Green, Reference Higgins and Green2008). This tool evaluates the following properties of studies: method of random sequence generation, concealment of allocation, blinding, incomplete outcome data, selective outcome reporting, and other potential sources of bias including sponsorship bias (i.e. whether the funding source could have led to a potential financial conflict of interest). Each item was rated as being potentially at low risk of bias (“Yes”), high risk of bias (“No”), or unclear. All items were rated in duplicate by two authors.

Data synthesis

Information on study characteristics, assessment of study quality, and efficacy and safety outcomes was summarized in tables. We summarized the effects of pharmacological interventions by medication class. The studies that reported on both antipsychotics and another active comparator were described in the non-antipsychotic category (e.g. studies comparing antipsychotics and cholinesterase inhibitors were described under the cholinesterase inhibitor section).

Results

Study selection

The flow of studies through the review process is summarized in Figure 1. A total of 8,342 citations were identified through searches of electronic databases and 315 full-text articles were retrieved and reviewed. From these articles, 29 studies were identified that met our inclusion criteria.

Figure 1. Flow of studies through the review process.

Characteristics of included studies

The 29 studies meeting inclusion criteria encompassed 19 studies of antipsychotics (Barnes et al., Reference Barnes, Veith and Okimoto1982; Cantillon et al., Reference Cantillon, Brunswick, Molina and Bahro1996; De Deyn et al., Reference De Deyn1999; Reference De Deyn2004; Katz et al., Reference Katz, Jeste, Mintzer, Clyde, Napolitano and Brecher1999; Street et al., Reference Street2000; Gaber et al., Reference Gaber, Ronzoli, Bruno and Biagi2001; Brodaty et al., Reference Brodaty2003; Fontaine et al., Reference Fontaine, Hynan, Koch, Martin-Cook, Svetlik and Weiner2003; Ballard et al., Reference Ballard2005; Mintzer et al., Reference Mintzer2006; Reference Mintzer2007; Tariot et al., Reference Tariot2006; Verhey et al., Reference Verhey, Verkaaik and Lousberg2006; Holmes et al., Reference Holmes2007; Huertas et al., Reference Huertas2007; Zhong et al., Reference Zhong, Tariot, Mintzer, Minkwitz and Devine2007; Streim et al., Reference Streim2008; Rappaport et al., Reference Rappaport, Marcus, Manos, McQuade and Oren2009) (15 studies of atypical antipsychotics (De Deyn et al., Reference De Deyn1999; Reference De Deyn2004; Katz et al., Reference Katz, Jeste, Mintzer, Clyde, Napolitano and Brecher1999; Street et al., Reference Street2000; Brodaty et al., Reference Brodaty2003; Fontaine et al., Reference Fontaine, Hynan, Koch, Martin-Cook, Svetlik and Weiner2003; Ballard et al., Reference Ballard2005; Mintzer et al., Reference Mintzer2006; Reference Mintzer2007; Tariot et al., Reference Tariot2006; Verhey et al., Reference Verhey, Verkaaik and Lousberg2006; Holmes et al., Reference Holmes2007; Zhong et al., Reference Zhong, Tariot, Mintzer, Minkwitz and Devine2007; Streim et al., Reference Streim2008; Rappaport et al., Reference Rappaport, Marcus, Manos, McQuade and Oren2009) and seven of typical antipsychotics (Barnes et al., Reference Barnes, Veith and Okimoto1982; Cantillon et al., Reference Cantillon, Brunswick, Molina and Bahro1996; De Deyn et al., Reference De Deyn1999; Gaber et al., Reference Gaber, Ronzoli, Bruno and Biagi2001; Tariot et al., Reference Tariot2006; Verhey et al., Reference Verhey, Verkaaik and Lousberg2006; Huertas et al., Reference Huertas2007)), three studies of cholinesterase inhibitors (Tariot et al., Reference Tariot2001; Ballard et al., Reference Ballard2005; Holmes et al., Reference Holmes2007), four studies of anticonvulsants (Tariot et al., Reference Tariot1998; Reference Tariot2005; Porsteinsson et al., Reference Porsteinsson2001; Sommer et al., Reference Sommer, Aga, Cvancarova, Olsen, Selbaek and Engedal2009), one study of antidepressants (Gaber et al., Reference Gaber, Ronzoli, Bruno and Biagi2001), and seven studies evaluating medications from other classes (Cantillon et al., Reference Cantillon, Brunswick, Molina and Bahro1996; Kyomen et al., Reference Kyomen, Satlin, Hennen and Wei1999; Hall et al., Reference Hall, Keks and O'Connor2005; Peskind et al., Reference Peskind2005; Huertas et al., Reference Huertas2007; Gehrman et al., Reference Gehrman, Connor, Martin, Shochat, Corey-Bloom and Ancoli-Israel2009; Wang et al., Reference Wang2009) (Table 1). Of these studies, 20 were placebo-controlled (Barnes et al., Reference Barnes, Veith and Okimoto1982; Tariot et al., Reference Tariot1998; Reference Tariot2001; Reference Tariot2005; De Deyn et al., Reference De Deyn1999; Reference De Deyn2004; Katz et al., Reference Katz, Jeste, Mintzer, Clyde, Napolitano and Brecher1999; Kyomen et al., Reference Kyomen, Satlin, Hennen and Wei1999; Street et al., Reference Street2000; Porsteinsson et al., Reference Porsteinsson2001; Brodaty et al., Reference Brodaty2003; Ballard et al., Reference Ballard2005; Hall et al., Reference Hall, Keks and O'Connor2005; Peskind et al., Reference Peskind2005; Mintzer et al., Reference Mintzer2006; Reference Mintzer2007; Tariot et al., Reference Tariot2006; Zhong et al., Reference Zhong, Tariot, Mintzer, Minkwitz and Devine2007; Streim et al., Reference Streim2008; Gehrman et al., Reference Gehrman, Connor, Martin, Shochat, Corey-Bloom and Ancoli-Israel2009; Rappaport et al., Reference Rappaport, Marcus, Manos, McQuade and Oren2009; Sommer et al., Reference Sommer, Aga, Cvancarova, Olsen, Selbaek and Engedal2009; Wang et al., Reference Wang2009), and 11 compared two medications within the same trial (Barnes et al., Reference Barnes, Veith and Okimoto1982; Cantillon et al., Reference Cantillon, Brunswick, Molina and Bahro1996; De Deyn et al., Reference De Deyn1999; Gaber et al., Reference Gaber, Ronzoli, Bruno and Biagi2001; Fontaine et al., Reference Fontaine, Hynan, Koch, Martin-Cook, Svetlik and Weiner2003; Ballard et al., Reference Ballard2005; Tariot et al., Reference Tariot2006; Verhey et al., Reference Verhey, Verkaaik and Lousberg2006; Holmes et al., Reference Holmes2007; Huertas et al., Reference Huertas2007). All of the studies used oral formulations of medications except for one trial that utilized intramuscular aripiprazole (Rappaport et al., Reference Rappaport, Marcus, Manos, McQuade and Oren2009) and one study of transdermal estrogen (Hall et al., Reference Hall, Keks and O'Connor2005). A total of 4,954 individuals were included with a median study sample size of 76 (range = 14–625 participants per trial). The median age of participants in studies was 83 years and 71% were women in studies reporting the gender distribution. Most study participants had moderate to severe dementia with average Mini-Mental State Examination (MMSE) scores of between 5 and 14. The median trial duration was 56 days (range = 1–90 days). A variety of outcome measures were reported in studies including composite measures of NPS (Barnes et al., Reference Barnes, Veith and Okimoto1982; Cantillon et al., Reference Cantillon, Brunswick, Molina and Bahro1996; Tariot et al., Reference Tariot1998; Reference Tariot2001; Reference Tariot2005; Reference Tariot2006; De Deyn et al., Reference De Deyn1999; Reference De Deyn2004; Katz et al., Reference Katz, Jeste, Mintzer, Clyde, Napolitano and Brecher1999; Street et al., Reference Street2000; Porsteinsson et al., Reference Porsteinsson2001; Fontaine et al., Reference Fontaine, Hynan, Koch, Martin-Cook, Svetlik and Weiner2003; Peskind et al., Reference Peskind2005; Gehrman et al., Reference Gehrman, Connor, Martin, Shochat, Corey-Bloom and Ancoli-Israel2009; Sommer et al., Reference Sommer, Aga, Cvancarova, Olsen, Selbaek and Engedal2009; Wang et al., Reference Wang2009), agitation (Gaber et al., Reference Gaber, Ronzoli, Bruno and Biagi2001; Ballard et al., Reference Ballard2005; Verhey et al., Reference Verhey, Verkaaik and Lousberg2006; Holmes et al., Reference Holmes2007; Zhong et al., Reference Zhong, Tariot, Mintzer, Minkwitz and Devine2007; Rappaport et al., Reference Rappaport, Marcus, Manos, McQuade and Oren2009,), aggression (Kyomen et al., Reference Kyomen, Satlin, Hennen and Wei1999; Brodaty et al., Reference Brodaty2003; Hall et al., Reference Hall, Keks and O'Connor2005; Huertas et al., Reference Huertas2007), or psychosis (Mintzer et al., Reference Mintzer2006; Reference Mintzer2007; Streim et al., Reference Streim2008).

Table 1. Included studies of pharmacological interventions for long-term care residents with dementia

*p < 0.05 when compared with placebo or other comparator medication in the study; – = not reported.

ACES = Agitation–Calmness Evaluation Scale; AD = Alzheimer's disease; BEHAVE-AD = Behavioral Pathology in Alzheimer's Disease; BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression; CMAI = Cohen-Mansfield Agitation Inventory; DSM = Diagnostic and Statistical Manual of Mental Disorders; ICD = International Classification of Disease; NH = nursing home; MMSE = Mini-Mental State Examination; NINCDS–ADRDA = National Institutes of Neurological and Communicative Disorders and Stroke – Alzheimer's Disease and Related Disorders Association; NPI = Neuropsychiatric Inventory; OAS = Overt Aggression Scale; PANSS-EC = Positive and Negative Syndrome Scale – Excited Component; RAGE = Rating Scale for Aggressive Behavior in the Elderly; SIB = Severe Impairment Battery; SOAS = Staff Observation Aggression Scale.

Efficacy of interventions on neuropsychiatric symptoms of dementia

The efficacy of pharmacological interventions for NPS is summarized in Table 1.

Antipsychotics

The 15 studies of atypical antipsychotics involved risperidone (N = 6), olanzapine (N = 4), quetiapine (N = 3), and aripiprazole (N = 3). Statistically significant results on change in NPS scores compared with placebo were noted in two studies of risperidone (Katz et al., Reference Katz, Jeste, Mintzer, Clyde, Napolitano and Brecher1999; Brodaty et al., Reference Brodaty2003), two studies of olanzapine (Street et al., Reference Street2000; De Deyn et al., Reference De Deyn2004), and one study of aripiprazole (Mintzer et al., Reference Mintzer2007). One study comparing risperidone and olanzapine found no statistically significant difference between the two groups (Fontaine et al., Reference Fontaine, Hynan, Koch, Martin-Cook, Svetlik and Weiner2003). Olanzapine and haloperidol were both associated with reductions in agitation and NPS with no significant differences between groups (Verhey et al., Reference Verhey, Verkaaik and Lousberg2006). Risperidone was associated with greater reductions in agitation when compared with rivastigmine in one study (Holmes et al., Reference Holmes2007). One study also found no significant differences when either quetiapine or rivastigmine was compared with placebo (Ballard et al., Reference Ballard2005). A trial of quetiapine, haloperidol, and placebo found no difference between either of the two active treatment groups and placebo in measures of NPS (Tariot et al., Reference Tariot2006). A single trial compared the typical antipsychotics loxapine, thioridazine, and placebo and found no benefit for either medication over placebo (Barnes et al., Reference Barnes, Veith and Okimoto1982).

Eight studies reported change in NPS using dichotomized outcomes. Risperidone was associated with overall clinical improvement in NPS when compared with placebo in two studies (Brodaty et al., Reference Brodaty2003; Mintzer et al., Reference Mintzer2006) and significant reduction in NPS in a second study (Katz et al., Reference Katz, Jeste, Mintzer, Clyde, Napolitano and Brecher1999). However, a third study did not find any difference in response rates for risperidone compared with either haloperidol or placebo (De Deyn et al., Reference De Deyn1999). Olanzapine at doses of 5 and 10 mg daily were more likely to produce significant reductions in NPS when compared with placebo, although the 15 mg dose was not better than placebo (Street et al., Reference Street2000). Aripiprazole was associated with a greater response rate than placebo in one study (Streim et al., Reference Streim2008), while a second study did not find any difference in response (Mintzer et al., Reference Mintzer2007). Quetiapine at 200 mg daily was found to be associated with a higher proportion of individuals with significant global improvement than placebo in one study, while 100 mg was not associated with significant benefit (Zhong et al., Reference Zhong, Tariot, Mintzer, Minkwitz and Devine2007).

Cholinesterase inhibitors

One study of donepezil found no benefit for the medication when compared with placebo on measures of NPS (Tariot et al., Reference Tariot2001). Two studies evaluated the cholinesterase inhibitor rivastigmine (Ballard et al., Reference Ballard2005; Holmes et al., Reference Holmes2007), with there being no benefit for rivastigmine when compared with placebo (Ballard et al., Reference Ballard2005), or the atypical antipsychotics quetiapine (Ballard et al., Reference Ballard2005) or risperidone (Holmes et al., Reference Holmes2007).

Anticonvulsants

Of the four placebo-controlled studies involving anticonvulsants, one evaluated carbamazepine (Tariot et al., Reference Tariot1998), two examined divalproex sodium (Porsteinsson et al., Reference Porsteinsson2001; Tariot et al., Reference Tariot2005), and one study examined oxcarbazepine (Sommer et al., Reference Sommer, Aga, Cvancarova, Olsen, Selbaek and Engedal2009). Only carbamazepine was associated with a statistically significant reduction in NPS symptoms (Tariot et al., Reference Tariot1998) while the other studies showed no benefit for other anticonvulsants compared with placebo (Porsteinsson et al., Reference Porsteinsson2001; Tariot et al., Reference Tariot2005; Sommer et al., Reference Sommer, Aga, Cvancarova, Olsen, Selbaek and Engedal2009).

Antidepressants

A single small study compared sertraline with haloperidol on NPS and found that both groups had a non-significant reduction in NPS with no difference between groups (Gaber et al., Reference Gaber, Ronzoli, Bruno and Biagi2001).

Other medications

A study comparing buspirone and haloperidol found no significant difference between the two groups on symptoms of NPS (Cantillon et al., Reference Cantillon, Brunswick, Molina and Bahro1996). Two placebo-controlled studies evaluated the effects of estrogen therapy on NPS, one with oral estrogen (Kyomen et al., Reference Kyomen, Satlin, Hennen and Wei1999) and a second with a transdermal estrogen patch (Hall et al., Reference Hall, Keks and O'Connor2005), with only the study in which estrogen was administered orally demonstrating benefit over placebo. A single trial of the androgen antagonist cyproterone acetate compared with haloperidol and found that cyproterone was associated with greater improvement in NPS (Huertas et al., Reference Huertas2007). A placebo-controlled trial of the β-adrenergic antagonist propranolol demonstrated improvement in NPS symptoms scores and global improvement in NPS (Peskind et al., Reference Peskind2005). One study of the α-1 adrenergic antagonist prazosin demonstrated benefits on NPS when compared with placebo (Wang et al., Reference Wang2009). A placebo-controlled study of melatonin did not demonstrate any benefit for NPS (Gehrman et al., Reference Gehrman, Connor, Martin, Shochat, Corey-Bloom and Ancoli-Israel2009).

Safety and tolerability

A total of 24 studies reported on trial withdrawals due to any cause (Tariot et al., Reference Tariot1998; Reference Tariot2001; Reference Tariot2005; Reference Tariot2006; De Deyn et al., Reference De Deyn1999; Reference De Deyn2004; Katz et al., Reference Katz, Jeste, Mintzer, Clyde, Napolitano and Brecher1999; Kyomen et al., Reference Kyomen, Satlin, Hennen and Wei1999; Street et al., Reference Street2000; Porsteinsson et al., Reference Porsteinsson2001; Brodaty et al., Reference Brodaty2003; Fontaine et al., Reference Fontaine, Hynan, Koch, Martin-Cook, Svetlik and Weiner2003; Ballard et al., Reference Ballard2005; Peskind et al., Reference Peskind2005; Mintzer et al., Reference Mintzer2006; Reference Mintzer2007; Huertas et al., Reference Huertas2007; Streim et al., Reference Streim2008; Gehrman et al., Reference Gehrman, Connor, Martin, Shochat, Corey-Bloom and Ancoli-Israel2009; Rappaport et al., Reference Rappaport, Marcus, Manos, McQuade and Oren2009; Sommer et al., Reference Sommer, Aga, Cvancarova, Olsen, Selbaek and Engedal2009; Wang et al., Reference Wang2009), 21 studies reported on trial withdrawals due to adverse events (Tariot et al., Reference Tariot1998; Reference Tariot2001; Reference Tariot2005; Reference Tariot2006; Katz et al., Reference Katz, Jeste, Mintzer, Clyde, Napolitano and Brecher1999; Kyomen et al., Reference Kyomen, Satlin, Hennen and Wei1999; Street et al., Reference Street2000; Porsteinsson et al., Reference Porsteinsson2001; Brodaty et al., Reference Brodaty2003; Fontaine et al., Reference Fontaine, Hynan, Koch, Martin-Cook, Svetlik and Weiner2003; De Deyn et al., Reference De Deyn2004; Ballard et al., Reference Ballard2005; Peskind et al., Reference Peskind2005; Mintzer et al., Reference Mintzer2006; Reference Mintzer2007; Huertas et al., Reference Huertas2007; Zhong et al., Reference Zhong, Tariot, Mintzer, Minkwitz and Devine2007; Streim et al., Reference Streim2008; Gehrman et al., Reference Gehrman, Connor, Martin, Shochat, Corey-Bloom and Ancoli-Israel2009; Rappaport et al., Reference Rappaport, Marcus, Manos, McQuade and Oren2009; Sommer et al., Reference Sommer, Aga, Cvancarova, Olsen, Selbaek and Engedal2009), and 23 studies reported mortality rates (Tariot et al., Reference Tariot1998; Reference Tariot2001; Reference Tariot2005; Reference Tariot2006; Katz et al., Reference Katz, Jeste, Mintzer, Clyde, Napolitano and Brecher1999; Kyomen et al., Reference Kyomen, Satlin, Hennen and Wei1999; Street et al., Reference Street2000; Porsteinsson et al., Reference Porsteinsson2001; Brodaty et al., Reference Brodaty2003; Fontaine et al., Reference Fontaine, Hynan, Koch, Martin-Cook, Svetlik and Weiner2003; De Deyn et al., Reference De Deyn2004; Ballard et al., Reference Ballard2005; Hall et al., Reference Hall, Keks and O'Connor2005; Peskind et al., Reference Peskind2005; Mintzer et al., Reference Mintzer2006; Reference Mintzer2007; Huertas et al., Reference Huertas2007; Zhong et al., Reference Zhong, Tariot, Mintzer, Minkwitz and Devine2007; Streim et al., Reference Streim2008; Gehrman et al., Reference Gehrman, Connor, Martin, Shochat, Corey-Bloom and Ancoli-Israel2009; Rappaport et al., Reference Rappaport, Marcus, Manos, McQuade and Oren2009; Sommer et al., Reference Sommer, Aga, Cvancarova, Olsen, Selbaek and Engedal2009; Wang et al., Reference Wang2009) (Table 1). Trial withdrawals due to any cause or adverse events were common in many studies. One risperidone trial found that the 2 mg dose was associated with higher rates of overall trial withdrawals and trial withdrawals due to adverse events compared with placebo, while mortality was higher with 1 mg daily when compared with placebo (Katz et al., Reference Katz, Jeste, Mintzer, Clyde, Napolitano and Brecher1999). Olanzapine at 15 mg daily was associated with higher rates of withdrawal due to adverse events although lower doses were not significantly different from placebo (Street et al., Reference Street2000). Only the 10 mg dose of aripiprazole was associated with an increased risk of adverse events when compared with placebo in one study (Mintzer et al., Reference Mintzer2007), while a second of aripiprazole found that overall rates of trial withdrawal were higher with aripiprazole (Streim et al., Reference Streim2008). Both quetiapine and rivastigmine were associated with higher rates of withdrawal than placebo in one study (Ballard et al., Reference Ballard2005) as was oxcarbazepine when compared with placebo (Sommer et al., Reference Sommer, Aga, Cvancarova, Olsen, Selbaek and Engedal2009). One study of propranolol found lower rates of trial withdrawals associated with drug treatment when compared with placebo (Peskind et al., Reference Peskind2005).

Quality of studies

In general, most studies were rated as being at low or unclear risk of bias due to various aspects related to study design (Table 2). Only one study was rated as being at low risk of bias on all the risk of bias items (Ballard et al., Reference Ballard2005). For the assessment of potential risk of bias associated with the study sponsor, 14 studies were funded by pharmaceutical companies, including 12 studies sponsored by the manufacturers of atypical antipsychotics (De Deyn et al., Reference De Deyn1999; Reference De Deyn2004; Katz et al., Reference Katz, Jeste, Mintzer, Clyde, Napolitano and Brecher1999; Street et al., Reference Street2000; Brodaty et al., Reference Brodaty2003; Fontaine et al., Reference Fontaine, Hynan, Koch, Martin-Cook, Svetlik and Weiner2003; Mintzer et al., Reference Mintzer2006; Reference Mintzer2007; Tariot et al., Reference Tariot2006; Zhong et al., Reference Zhong, Tariot, Mintzer, Minkwitz and Devine2007; Streim et al., Reference Streim2008; Rappaport et al., Reference Rappaport, Marcus, Manos, McQuade and Oren2009), one study of typical antipsychotics (Barnes et al., Reference Barnes, Veith and Okimoto1982), and one study of cholinesterase inhibitors (Tariot et al., Reference Tariot2001).

Table 2. Risk of bias assessment for pharmacological treatment of neuropsychiatric symptoms of dementia

Discussion

Our review identified a number of RCTs evaluating a variety of medications for the management of NPS in LTC settings. Overall, the most frequently studied class of medications was atypical antipsychotics. There is some evidence to support the efficacy of the atypical antipsychotics risperidone, olanzapine, and aripiprazole when compared with placebo on change in NPS symptom scores. There were additional single small positive studies with carbamazepine, estrogen, cyproterone acetate, propranolol, and prazosin. The effects of medications tended to be clinically modest and only a few studies reported on the rates of clinically significant outcomes such as symptom remission. Some medications may be effective in reducing overall levels of NPS and specific NPS including agitation and aggression. The risk of bias for these studies varied, although many studies had some potentially important methodological limitations. Trial withdrawals, adverse events, and mortality were relatively common outcomes in many studies. Importantly, there were no studies comparing pharmacological agents to non-pharmacological approaches and a limited number of studies directly comparing different pharmacological agents.

The findings of our review of pharmacological treatments for NPS in LTC are consistent with previous broader reviews of antipsychotics and other medications for the treatment of NPS (Schneider et al., Reference Schneider, Pollock and Lyness1990; Reference Schneider2006a; Borson and Raskind, Reference Borson and Raskind1997; Lanctot et al., Reference Lanctot1998; Sutor et al., Reference Sutor, Rummans and Smith2001; Kindermann et al., Reference Kindermann, Dolder, Bailey, Katz and Jeste2002; Snowden et al., Reference Snowden, Sato and Roy-Byrne2003; Alexopoulos et al., Reference Alexopoulos, Jeste, Chung, Carpenter, Ross and Docherty2005; Sink et al., Reference Sink, Holden and Yaffe2005; Ballard and Howard, Reference Ballard and Howard2006; Kozman et al., Reference Kozman, Wattis and Curran2006; Herrmann and Lanctot, Reference Herrmann and Lanctot2007; Konavalov et al., Reference Konavalov, Muralee and Tampi2007; Saddichha and Pandey, Reference Saddichha and Pandey2008; Ballard et al., Reference Ballard, Corbett, Chitramohan and Aarsland2009a; Reference Ballard2009b; Conn and Seitz, Reference Conn and Seitz2010). The atypical antipsychotics (in particular risperidone, olanzapine, and aripiprazole) appear to have the most extensive evidence in favor of their use for NPS, although even this evidence is limited to a relatively small number of studies. There was only one study that directly compared two atypical antipsychotics with no statistically significant difference in NPS outcomes when comparing risperidone with olanzapine (Fontaine et al., Reference Fontaine, Hynan, Koch, Martin-Cook, Svetlik and Weiner2003). Results from a large RCT comparing olanzapine, risperidone, quetiapine, and placebo for outpatients with Alzheimer's disease found that the primary outcome of time to discontinuation of treatment due to any cause did not differ between any of the three active treatment groups compared with placebo. However, time to discontinuation due to lack of efficacy favored both risperidone and olanzapine in this study (Schneider et al., Reference Schneider2006b). While most studies evaluated the effects of atypical antipsychotics on overall change in NPS, they appear to be most effective in reducing particular symptoms such as hostility, anger, and psychosis (Sultzer et al., Reference Sultzer2008). Although statistically significant results were observed in several studies in our review, clinically significant outcomes such as response rates or global clinical impression of change were only reported in a few studies.

Although there were few statistically significant differences noted on most safety outcomes, this is likely due to the limited power of many studies to detect adverse events associated with therapies. Existing meta-analyses and observational studies have however demonstrated major safety concerns with the use of atypical antipsychotics and other medications for NPS. Meta-analyses have demonstrated that atypical antipsychotics are associated with an increased risk of death (Schneider et al., Reference Schneider, Dagerman and Insel2005) with an odds ratio of 1.54, and an absolute risk difference of approximately 1% from studies conducted in LTC and other settings. Observational studies have also found an increased risk of mortality (Gill et al., Reference Gill2007). Similarly, an increased risk of major cerebrovascular events associated with antipsychotics use has been observed in meta-analyses of RCTs (Herrmann and Lanctot, Reference Herrmann and Lanctot2005), with a relative risk of 2.7 and an absolute risk difference of approximately 1%. Other less serious, but more common side effects associated with atypical antipsychotics include increased rates of somnolence (Schneider et al., Reference Schneider, Dagerman and Insel2006a), falls (Hien Le et al., Reference Hien Le2005), and fall-related injuries including hip fractures (Jalbert et al., Reference Jalbert, Eaton, Miller and Lapane2010), which must also be monitored during therapy. There is also an increasing appreciation of the effects of atypical antipsychotics on cognitive and functional decline in older adults with dementia (Vigen et al., Reference Vigen2011).

There were relatively few studies that examined medications other than atypical antipsychotics. Some typical antipsychotics may also be effective for NPS (Schneider et al., Reference Schneider, Pollock and Lyness1990; Lanctot et al., Reference Lanctot1998), although these medications are no more effective than atypical antipsychotics and are associated with higher rates of adverse events (De Deyn et al., Reference De Deyn1999; Verhey et al., Reference Verhey, Verkaaik and Lousberg2006; Tariot et al., Reference Tariot2006). The risk of death (Wang et al., Reference Wang2005; Gill et al., Reference Gill2007) and stroke (Herrmann et al., Reference Herrmann, Mamdani and Lanctot2004; Gill et al., Reference Gill2005) associated with typical antipsychotics is similar to or greater than the risk observed with atypical antipsychotics. There was only a single small study of antidepressants for NPS conducted in LTC, although there is growing interest in the use of antidepressants for this indication (Seitz et al., Reference Seitz, Adenuri, Gill, Gruneir, Herrmann and Rochon2011). Recent RCTs of the antidepressant citalopram and escitalopram have indicated that these medications may be as effective as the antipsychotics risperidone (Pollock et al., Reference Pollock2007) or perphenazine (Pollock et al., Reference Pollock2002) and more effective than placebo (Pollock et al., Reference Pollock2002) in hospitalized inpatient populations. Importantly, the rates of adverse events with antidepressants may be less than that observed with antipsychotics (Pollock et al., Reference Pollock2007; Barak et al., Reference Barak, Plopski, Tadger and Paleacu2011). However, serotonergic antidepressants have been associated with serious adverse events in older adults including falls (Vestergaard et al., Reference Vestergaard, Rejnmark and Mosekilde2006), fractures (Takkouche et al., Reference Takkouche, Montes-Martinez, Gill and Etminan2007), bleeding (Andrade et al., Reference Andrade, Sandarsh, Chethan and Nagesh2010), and hyponatremia (Fabian et al., Reference Fabian2004). Some observational studies have also reported that antidepressants may be associated with an increased risk of death (Huybrechts et al., Reference Huybrechts, Rothman, Silliman, Brookhart and Schneeweiss2011) and stroke (Trifiro et al., Reference Trifiro, Dieleman, Sen, Gambassi and Sturkenboom2010; Wu et al., Reference Wu, Wang, Cheng and Gau2011), although not all studies have confirmed these associations (Kales et al., Reference Kales2007). The anticonvulsant carbamazepine demonstrated benefit in terms of reduction of agitation in a single small study conducted in LTC (Tariot et al., Reference Tariot1998) as well as two other small trials conducted outside of LTC (Cooney et al., Reference Cooney, Mortimer, Smith, Newton and Wrigley1996; Olin et al., Reference Olin, Fox, Pawluczyk, Taggart and Schneider2001). Other medications reporting benefit were represented by single small studies and these agents may be considered for some individuals who do not tolerate or fail to respond to other treatments, although further research is needed to establish their efficacy and safety. Divalproex sodium was not effective at reducing NPS in studies included in our review (Porsteinsson et al., Reference Porsteinsson2001; Tariot et al., Reference Tariot2005) and other studies have demonstrated that valproic acid may accelerate cognitive decline (Tariot et al., Reference Tariot2011) and, as such, these medications should be avoided in patients with NPS. Studies of cholinesterase inhibitors for the treatment of NPS did not find that these medications were effective in reducing NPS among patients with significant symptoms (Tariot et al., Reference Tariot2001; Ballard et al., Reference Ballard2005; Holmes et al., Reference Holmes2007), which has also been observed in trials conducted in community-based populations (Howard et al., Reference Howard2007).

Although most of the trials in our review were between 6 and 12 weeks in length, in clinical practice antipsychotics are often prescribed for prolonged periods of time in LTC (Ballard et al., Reference Ballard2004; Ruths et al., Reference Ruths, Straand, Nygaard, Bjorvatn and Pallesen2004; Gill et al., Reference Gill2007). The risk of adverse events associated with antipsychotics are greatest after initiating treatment (Gill et al., Reference Gill2007), although chronic therapy is also associated with risks (Ballard et al., Reference Ballard2008). A placebo-controlled trial comparing continuation of antipsychotic therapy to placebo for LTC residents with NPS found that a decreased risk of mortality was associated with cessation of antipsychotics when compared with continued use (Ballard et al., Reference Ballard2009c). Discontinuation of antipsychotic therapy did not result in worsening of NPS for most individuals (Ballard et al., Reference Ballard2008). Additional RCTs have demonstrated that antipsychotics can be discontinued in the majority of individuals receiving chronic antipsychotic therapy without worsening of behavior (Cohen-Mansfield et al., Reference Cohen-Mansfield, Lipson, Werner, Billig, Taylor and Woosley1999; van Reekum et al., Reference Van Reekum, Clarke, Conn, Hermann, Eryavec, Cohen and Ostrander2002; Ballard et al., Reference Ballard2004; Ruths et al., Reference Ruths, Straand, Nygaard, Bjorvatn and Pallesen2004; Reference Ruths, Straand, Nygaard and Aarsland2008). Predictors of successful discontinuation of therapy include lower baseline severity of NPS (Ballard et al., Reference Ballard2004; Reference Ballard2008) and lower dosages of antipsychotics to achieve symptom control (van Reekum et al., Reference Van Reekum, Clarke, Conn, Hermann, Eryavec, Cohen and Ostrander2002; Ruths et al., Reference Ruths, Straand, Nygaard and Aarsland2008).

There are some limitations to our review. One limitation relates to the method by which NPS were assessed, that being by retrospective questionnaire ratings of NPS as reported by nursing staff or other caregivers. Direct observations of behaviors would be considered the “gold standard” method for measuring NPS although studies have demonstrated that directly observed levels of agitation and questionnaire reported agitation are only moderately correlated (Cohen-Mansfield and Libin, Reference Cohen-Mansfield and Libin2004). However, direct measures of NPS are too labor intensive to be used as outcome measures in large clinical studies and questionnaire reports of behavior are more feasible to use in this setting. We only focused on published English-language studies and there are additional unpublished studies that have been identified (Schneider et al., Reference Schneider, Dagerman and Insel2006a), which may have introduced a publication bias in favor of studies showing benefits with medications (Turner et al., Reference Turner, Matthews, Linardatos, Tell and Rosenthal2008). Many of the studies in our review were sponsored by pharmaceutical companies and studies that are sponsored by pharmaceutical companies are more likely to report outcomes in favor of the company's product than studies funded by other sources (Lexchin et al., Reference Lexchin, Bero, Djulbegovic and Clark2003). Finally, due to the range of medications, outcome measures, and clinical populations, we did not undertake meta-analysis to quantitatively summarize the effects of medications.

Particular strengths of our review should be highlighted. First, we restricted our review to randomized controlled clinical trials to evaluate only the highest level of evidence. We also included only those studies conducted in LTC settings and so the results observed should be generalizable to other LTC populations. Our review also assessed the quality of included studies to identify potential sources of bias which may influence the internal validity of the primary studies. Finally, we undertook a detailed examination of the efficacy and safety of medications to allow clinicians to better appreciate and communicate the potential benefits and risks of various treatments.

Conclusions

The best supported evidence for management of NPS in LTC is for some atypical antipsychotics in particular risperidone, olanzapine, and aripiprazole. There are relatively few studies of other medications which have sufficient evidence base to support their use. However, the known risks of adverse events associated with antipsychotics and other psychotropic medications in LTC highlight the need for safe and effective alternatives to antipsychotics and existing pharmacological treatments. Non-pharmacological interventions should continue to be used as initial treatments for NPS where these are available, also taking into consideration patient and caregivers priorities. Further research into the comparative effectiveness of pharmacological treatments and non-pharmacological treatments is required to further understand the relative risks and benefits of treatments for NPS in LTC.

Conflict of interest

Dr. Herrmann has received grants or research funds from Sonexa, Sonafi, Aventis, and Lundbeck, honoraria from Pfizer and Lundbeck, and served as a consultant for Lundbeck.

Description of authors’ roles

All authors made substantial contributions to the conception and design of the study and analysis and interpretation of data. Dr. Seitz and Ms. Brisbin and Ms. Rines contributed to the acquisition of studies and data extraction. All authors contributed to drafting the paper and revising it critically for intellectual content. All authors approved of the final version of the manuscript.

Acknowledgments

Dr. Seitz is supported by a Clinician Scientist Salary Support Award from Queen's University. This project was supported by a Canadian Institutes of Health Research Knowledge Synthesis Grant KRS#103345 “Interventions for neuropsychiatric symptoms of dementia in long-term care: a systematic review.”

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Figure 0

Figure 1. Flow of studies through the review process.

Figure 1

Table 1. Included studies of pharmacological interventions for long-term care residents with dementia

Figure 2

Table 2. Risk of bias assessment for pharmacological treatment of neuropsychiatric symptoms of dementia

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