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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 ,
Sudeep S. Gill ,
Nathan Herrmann ,
Sarah Brisbin ,
Mark J. Rapoport ,
Jenna Rines ,
Kimberley Wilson ,
Ken Le Clair  and
David K. Conn
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: [email protected]

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.

Keywords

dementiaAlzheimerlong-term carepharmacologicalmedications
Type
Review Article
Information
International Psychogeriatrics , Volume 25 , Issue 2 , February 2013 , pp. 185 - 203
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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.”

References

Alexopoulos, G. S., Jeste, D. V., Chung, H., Carpenter, D., Ross, R. and Docherty, J. P. (2005). The expert consensus guideline series. Treatment of dementia and its behavioral disturbances. Introduction: methods, commentary, and summary. Postgraduate Medicine, Spec No, 6.Google Scholar
Andrade, C., Sandarsh, S., Chethan, K. B. and Nagesh, K. S. (2010). Serontonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and reconsideration of mechanisms. Journal of Clinical Psychiatry, 71, 1565–1575.CrossRefGoogle Scholar
Ballard, C. and Howard, R. (2006). Neuroleptic drugs in dementia: benefits and harm. Nature Reviews Neuroscience, 7, 492–500.CrossRefGoogle ScholarPubMed
Ballard, C. and Waite, J. (2006). The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease. Cochrane Database of Systematic Reviews (Online), (1), CD003476.CrossRefGoogle Scholar
Ballard, C. G.et al. (2004). A 3-month, randomized, placebo-controlled, neuroleptic discontinuation study in 100 people with dementia: the neuropsychiatric inventory median cutoff is a predictor of clinical outcome. Journal of Clinical Psychiatry, 65, 114–119.CrossRefGoogle ScholarPubMed
Ballard, C.et al. (2005). Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial. British Medical Journal, 330, 874.CrossRefGoogle Scholar
Ballard, C.et al. (2008). A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (The DART-AD Trial). PLoS Medicine, 5, 0587–0599.CrossRefGoogle Scholar
Ballard, C., Corbett, A., Chitramohan, R. and Aarsland, D. (2009a). Management of agitation and aggression associated with Alzheimer's disease: controversies and possible solutions. Current Opinion in Psychiatry, 22, 532–540.CrossRefGoogle Scholar
Ballard, C.et al. (2009b). Management of agitation and aggression associated with Alzheimer disease. Nature Reviews Neurology, 5, 245–255.CrossRefGoogle Scholar
Ballard, C.et al. (2009c). The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. The Lancet Neurology, 8, 151–157.CrossRefGoogle Scholar
Barak, Y., Plopski, I., Tadger, S. and Paleacu, D. (2011). Escitalopram versus risperidone for the treatment of behavioral and psychotic symptoms associated with Alzheimer's disease: a randomized double-blind study. International Psychogeriatrics, 23, 1515–1519.CrossRefGoogle Scholar
Barnes, R., Veith, R. and Okimoto, J. (1982). Efficacy of antipsychotic medications in behaviorally disturbed dementia patients. American Journal of Psychiatry, 139, 1170–1174.Google Scholar
Bharani, N. and Snowden, M. (2005). Evidence-based interventions for nursing home residents with dementia-related behavioral symptoms. Psychiatric Clinics of North America, 28, 985–1005.CrossRefGoogle Scholar
Borson, S. and Raskind, M. A. (1997). Clinical features and pharmacologic treatment of behavioral symptoms of Alzheimer's disease. Neurology, 48, S17.CrossRefGoogle Scholar
Brodaty, H.et al. (2003). A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia. Journal of Clinical Psychiatry, 64, 134–143.CrossRefGoogle Scholar
Burns, B. J., Wagner, H. R., Taube, J. E., Magaziner, J., Permutt, T. and Landerman, L. R. (1993). Mental health service use by the elderly in nursing homes. American Journal of Public Health, 83, 331–337.CrossRefGoogle ScholarPubMed
Canadian Coalition for Seniors’ Mental Health (2006). National Guidelines for Seniors’ Mental Health: The Assessment and Treatment of Mental Health Issues in Long Term Care Homes. Ontario: Canadian Coalition for Seniors’ Mental Health.Google Scholar
Cantillon, M., Brunswick, R., Molina, D. and Bahro, M. (1996). Buspirone vs. haloperidol: a double-blind trial for agitation in a nursing home population with Alzheimer's disease. American Journal of Geriatric Psychiatry, 4, 263–267.CrossRefGoogle Scholar
Cohen-Mansfield, J. and Jensen, B. (2008). Nursing home physicians’ knowledge of and attitudes toward nonpharmacological interventions for treatment of behavioral disturbances associated with dementia. Journal of the American Medical Directors Association, 9, 491–498.CrossRefGoogle Scholar
Cohen-Mansfield, J. and Libin, A. (2004). Assessment of agitation in elderly patients with dementia: correlations between informant rating and direct observation. International Journal of Geriatric Psychiatry, 19, 881–889.CrossRefGoogle Scholar
Cohen-Mansfield, J. and Mintzer, J. E. (2005). Time for change: the role of nonpharmacological interventions in treating behavior problems in nursing home residents with dementia. Alzheimer Disease and Associated Disorders, 19, 37–40.CrossRefGoogle ScholarPubMed
Cohen-Mansfield, J., Lipson, S., Werner, P., Billig, N., Taylor, L. and Woosley, R. (1999). Withdrawal of haloperidol, thioridazine, and lorazepam in the nursing home. Archives of Internal Medicine, 159, 1733–1740.CrossRefGoogle ScholarPubMed
Cohen-Mansfield, J., Thein, K., Marx, M. S. and Dakheel-Ali, D. (2012). What are the barriers to performing nonpharmacological interventions for behavioral symptoms in the nursing home? Journal of the American Medical Directors Association, 13, 400–405.CrossRefGoogle Scholar
Conn, D. K. (Ed.). (1992). Mental health issues in long-term care facilities. In Practical Psychiatry in the Nursing Home: A Handbook for Staff. Ashland, OH: Hogrefe and Huber Publishers.Google Scholar
Conn, D. K. and Seitz, D. P. (2010). Advances in the treatment of psychiatric disorders in long-term care homes. Current Opinion in Psychiatry, 23, 516–521.CrossRefGoogle Scholar
Cooney, C., Mortimer, A., Smith, A., Newton, K. and Wrigley, M. (1996). Carbamazepine use in aggressive behaviour associated with senile dementia. International Journal of Geriatric Psychiatry, 11, 901–905.3.0.CO;2-7>CrossRefGoogle Scholar
De Deyn, P. P.et al. (1999 ). A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology, 53, 946–955.CrossRefGoogle Scholar
De Deyn, P. P.et al. (2004). Olanzapine versus placebo in the treatment of psychosis with or without associated behavioral disturbances in patients with Alzheimer's disease. International Journal of Geriatric Psychiatry, 19, 115–126.CrossRefGoogle Scholar
Fabian, T. J.et al. (2004). Paroxetine-induced hyponatremia in older adults. Archives of Internal Medicine, 164, 327–332.CrossRefGoogle ScholarPubMed
Fahey, T., Montgomery, A. A., Barnes, J. and Protheroe, J. (2003). Quality of care for elderly residents in nursing homes and elderly people living at home: controlled observational study. BMJ, 326, 580–584.CrossRefGoogle Scholar
Fontaine, C. S., Hynan, L. S., Koch, K., Martin-Cook, K., Svetlik, D. and Weiner, M. F. (2003). A double-blind comparison of olanzapine versus risperidone in the acute treatment of dementia-related behavioral disturbances in extended care facilities. Journal of Clinical Psychiatry, 64, 726–730.CrossRefGoogle Scholar
Gaber, S., Ronzoli, S., Bruno, A. and Biagi, A. (2001). Sertraline versus small doses of haloperidol in the treatment of agitated behavior in patients with dementia. Archives of Gerontology and Geriatrics, 33 (Suppl.), 159–162.CrossRefGoogle Scholar
Gauthier, S., Cummings, J., Ballard, C., Brodaty, H., Grossberg, G., Robert, P. and Lyketsos, C. (2010). Management of behavioral problems in Alzheimer's disease. International Psychogeriatrics, 22, 346–372.CrossRefGoogle Scholar
Gehrman, P. R., Connor, D. J., Martin, J. L., Shochat, T., Corey-Bloom, J. and Ancoli-Israel, S. (2009). Melatonin fails to improve sleep or agitation in double-blind randomized placebo-controlled trial of institutionalized patients with Alzheimer disease. American Journal of Geriatric Psychiatry, 17, 166–169.CrossRefGoogle Scholar
Gill, S. S.et al. (2005). Atypical antipsychotic drugs and risk of ischaemic stroke: population based retrospective cohort study. British Medical Journal, 330, 445.CrossRefGoogle ScholarPubMed
Gill, S. S.et al. (2007). Antipsychotic drug use and mortality in older adults with dementia. Annals of Internal Medicine, 146, 775–786.CrossRefGoogle Scholar
Gruber-Baldini, A. L., Boustani, M., Sloane, P. D. and Zimmerman, S. (2004). Behavioral symptoms in residential care/assisted living facilities: prevalence, risk factors, and medication management. Journal of the American Geriatrics Society, 52, 1610–1617.CrossRefGoogle Scholar
Hall, K. A., Keks, N. A. and O'Connor, D. W. (2005). Transdermal estrogen patches for aggressive behavior in male patients with dementia: a randomized, controlled trial. International Psychogeriatrics, 17, 165–178.CrossRefGoogle Scholar
Herrmann, N. and Lanctot, K. L. (2005). Do atypical antipsychotics cause stroke? CNS Drugs, 19, 91–103.CrossRefGoogle Scholar
Herrmann, N. and Lanctot, K. L. (2007). Pharmacologic management of neuropsychiatric symptoms of Alzheimer disease. Canadian Journal of Psychiatry (Revue canadienne de psychiatrie), 52, 630–646.CrossRefGoogle Scholar
Herrmann, N., Mamdani, M. and Lanctot, K. L. (2004). Atypical antipsychotics and risk of cerebrovascular accidents. American Journal of Psychiatry, 161, 1113.CrossRefGoogle Scholar
Herrmann, N., Gauthier, S. and Lysy, P. G. (2007). Clinical practice guidelines for severe Alzheimer's disease. Alzheimer's and Dementia, 3, 385–397.CrossRefGoogle Scholar
Hien Le, T. T.et al. (2005). Aytypical antipsychotic medications and risk of falls in residents of aged care facilities. Journal of the American Geriatrics Society, 53, 1290–1295.CrossRefGoogle Scholar
Higgins, J. P. T. and Green, S. (2008). Cochrane Handbook for Systematic Reviews of Interventions. Chichester, UK: Wiley.CrossRefGoogle Scholar
Holmes, C.et al. (2007). Risperidone and rivastigmine and agitated behaviour in severe Alzheimer's disease: a randomised double blind placebo controlled study. International Journal of Geriatric Psychiatry, 22, 380–381.CrossRefGoogle Scholar
Howard, R. J.et al. (2007). Donepezil for the treatment of agitation in Alzheimer's disease. New England Journal of Medicine, 357, 1382–1392.CrossRefGoogle Scholar
Huertas, D.et al. (2007). Antiaggressive effect of cyproterone versus haloperidol in Alzheimer's disease: a randomized double-blind pilot study. Journal of Clinical Psychiatry, 68, 439–444.CrossRefGoogle Scholar
Huybrechts, K. F., Rothman, K. J., Silliman, R. A., Brookhart, M. A. and Schneeweiss, S. (2011). Risk of death and hospital admission for major medical events after initiation of psychotropic medications in older adults admitted to nursing homes. Canadian Medical Association Journal, 183, E411–E419.Google Scholar
Jalbert, J. J., Eaton, C. B., Miller, S. C. and Lapane, K. L. (2010). Antipsychotic use and the risk of hip fracture among older adults afflicted with dementia. Journal of the American Medical Directors Association, 11, 120–127.CrossRefGoogle Scholar
Kales, H. C.et al. (2007). Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medications. American Journal of Psychiatry, 164, 1568–1576.CrossRefGoogle Scholar
Kales, H. C.et al. (2011). Trends in antipsychotic use in dementia 1999–2007. Archives of General Psychiatry, 68, 190–197.CrossRefGoogle Scholar
Katz, I. R., Jeste, D. V., Mintzer, J. E., Clyde, C., Napolitano, J. and Brecher, M. (1999). Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. Risperidone Study Group. Journal of Clinical Psychiatry, 60, 107–115.CrossRefGoogle Scholar
Kindermann, S. S., Dolder, C. R., Bailey, A., Katz, I. R. and Jeste, D. V. (2002). Pharmacological treatment of psychosis and agitation in elderly patients with dementia: four decades of experience. Drugs and Aging, 19, 257–276.CrossRefGoogle Scholar
Konavalov, S., Muralee, S. and Tampi, R. R. (2007). Anticonvulsants for the treatment of behavioral and psychological symptoms of dementia: a literature review. International Psychogeriatrics, 20, 293–308.Google Scholar
Kozman, M. N., Wattis, J. and Curran, S. (2006). Pharmacological management of behavioral and psychological disturbance in dementia. Human Psychopharmacology: Clinical and Experimental, 21, 1–12.CrossRefGoogle ScholarPubMed
Kyomen, H. H., Satlin, A., Hennen, J. and Wei, J. Y. (1999). Estrogen therapy and aggressive behavior in elderly patients with moderate-to-severe dementia. Results from a short-term, randomized, double-blind trial. American Journal of Geriatric Psychiatry, 7, 339–348.Google Scholar
Lanctot, K. L.et al. (1998). Efficacy and safety of neuroleptics in behavioral disorders associated with dementia. Journal of Clinical Psychiatry, 59, 550–561; quiz 562–563.CrossRefGoogle Scholar
Larrayadieu, A.et al. (2011). Associated factors with antipsychotic use in assisted living facilities: a cross-sectional study in 4367 residents. Age and Ageing, 40, 368–375.CrossRefGoogle Scholar
Lexchin, J., Bero, L. A., Djulbegovic, B. and Clark, O. (2003). Pharmaceutical industry sponsorship and research outcome and quality: systematic review. British Medical Journal, 326, 1167–1170.CrossRefGoogle ScholarPubMed
Meeks, S. (1996). Psychological consultation to nursing homes: description of a six-year practice. Psychotherapy, 33, 19–29.CrossRefGoogle Scholar
Mintzer, J.et al. (2006). Risperidone in the treatment of psychosis of Alzheimer disease: results from a prospective clinical trial. American Journal of Geriatric Psychiatry, 14, 280–291.CrossRefGoogle ScholarPubMed
Mintzer, J. E.et al. (2007). Aripiprazole for the treatment of psychoses in institutionalized patients with Alzheimer dementia: a multicenter, randomized, double-blind, placebo-controlled assessment of three fixed doses. American Journal of Geriatric Psychiatry, 15, 918–931.CrossRefGoogle ScholarPubMed
Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G. and The Prisma Group. (2009). Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLOS Medicine, 6, e1000097.CrossRefGoogle Scholar
Nijk, R. M., Zuidema, S. U. and Koopmans, R. T. C. M. (2009). Prevalence and correlates of psychotropic drug use in Dutch nursing-home patients with dementia. International Psychogeriatrics, 21, 485–493.CrossRefGoogle Scholar
Olin, J. T., Fox, L. S., Pawluczyk, S., Taggart, N. A. and Schneider, L. S. (2001). A pilot randomized trial of carbamazepine for behavioral symptoms in treatment-resistant outpatients with Alzheimer disease. American Journal of Geriatric Psychiatry, 9, 400–405.CrossRefGoogle Scholar
Peskind, E. R.et al. (2005). Propranolol for disruptive behaviors in nursing home residents with probable or possible Alzheimer disease: a placebo-controlled study. Alzheimer Disease and Associated Disorders, 19, 23–28.CrossRefGoogle Scholar
Pitkala, K. H., Laurila, J., Strandberg, T. and Tilvis, R. (2004). Behavioral symptoms and the administration of psychotropic drugs to aged patients with dementia in nursing homes and in acute geriatric wards. International Psychogeriatrics, 16, 61–74.CrossRefGoogle Scholar
Pollock, B. G.et al. (2002). Comparison of citalopram, perphenazine, and placebo for the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients. The American Journal of Psychiatry, 159, 460–465.CrossRefGoogle Scholar
Pollock, B. G.et al. (2007). A double-blind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia. American Journal of Geriatric Psychiatry, 15, 942–952.CrossRefGoogle ScholarPubMed
Porsteinsson, A. P.et al. (2001). Placebo-controlled study of divalproex sodium for agitation in dementia. American Journal of Geriatric Psychiatry, 9, 58–66.CrossRefGoogle Scholar
Rappaport, S. A., Marcus, R. N., Manos, G., McQuade, R. D. and Oren, D. A. (2009). A randomized, double-blind, placebo-controlled tolerability study of intramuscular aripiprazole in acutely agitated patients with Alzheimer's, vascular, or mixed dementia. Journal of the American Medical Directors Association, 10, 21–27.CrossRefGoogle Scholar
Reichman, W. E.et al. (1998). Psychiatric consultation in the nursing home: a survey of six states. American Journal of Geriatric Psychiatry, 6, 320–327.Google Scholar
Rochon, P. A.et al. (2007). Variation in nursing home antipsychotic prescribing rates. Archives of Internal Medicine, 167, 676–683.CrossRefGoogle ScholarPubMed
Rochon, P. A.et al. (2008). Antipsychotic therapy and short-term serious events in older adults with dementia. Archives of Internal Medicine, 168, 1090–1096.CrossRefGoogle Scholar
Ruths, S., Straand, J., Nygaard, H. A., Bjorvatn, B. and Pallesen, S. (2004). Effect of antipsychotic withdrawal on behavior and sleep/wake activity in nursing home residents with dementia: a randomized, placebo-controlled, double-blinded study the bergen district nursing home study. Journal of the American Geriatrics Society, 52, 1737–1743.CrossRefGoogle Scholar
Ruths, S., Straand, J., Nygaard, H. A. and Aarsland, D. (2008). Stopping antipsychotic drug therapy in demented nursing home patients: a randomized, placebo-controlled study – the Bergen District Nursing Home Study (BEDNURS). International Journal of Geriatric Psychiatry, 23, 889–895.CrossRefGoogle Scholar
Saddichha, S. and Pandey, V. (2008). Alzheimer's and non-Alzheimer's dementia: a critical review of pharmacological and nonpharmacological strategies. American Journal of Alzheimer's Disease and Other Dementias, 23, 150–161.CrossRefGoogle ScholarPubMed
Schneider, L. S., Dagerman, K. S. and Insel, P. (2005). Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. Journal of the American Medical Association, 294, 1934–1943.CrossRefGoogle Scholar
Schneider, L. S., Pollock, V. E. and Lyness, S. A. (1990). A metaanalysis of controlled trials of neuroleptic treatment in dementia. Journal of the American Geriatrics Society, 38, 553–563.CrossRefGoogle ScholarPubMed
Schneider, L. S., Dagerman, K. and Insel, P. S. (2006a). Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. American Journal of Geriatric Psychiatry, 14, 191–210.CrossRefGoogle ScholarPubMed
Schneider, L. S.et al. (2006b). Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. New England Journal of Medicine, 355, 1525–1538.CrossRefGoogle Scholar
Seitz, D. P., Gruneir, A., Conn, D. K. and Rochon, P. A. (2009). Cholinesterase inhibitor use in U.S. nursing homes: results from the National Nursing Home Survey. In American Association of Geriatric Psychiatry Annual Meeting. Honolulu, HA.Google Scholar
Seitz, D., Purandare, N. and Conn, D. (2010). Prevalence of psychiatric disorders among older adults in long-term care homes: a systematic review. International Psychogeriatrics, 22, 1025–1039.CrossRefGoogle Scholar
Seitz, D., Adenuri, N., Gill, S. S., Gruneir, A., Herrmann, N. and Rochon, P. A. (2011). Antidepressants for psychosis and agitation in dementia. Cochrane Database of Systematic Reviews, February 16, CD008191.CrossRefGoogle Scholar
Seitz, D. P.et al. (2012). Efficacy and feasibility of non-pharmacological interventions for neuropsychiatric symptoms of dementia in long-term care: a systematic review. Journal of the American Medical Directors Association, 13, 503–506.e2.CrossRefGoogle Scholar
Selbaek, G., Kirkevold, O. and Engedal, K. (2007). The prevalence of psychiatric symptoms and behavioural disturbances and the use of psychotropic drugs in Norwegian nursing homes. International Journal of Geriatric Psychiatry, 22, 843–849.CrossRefGoogle ScholarPubMed
Selbaek, G., Kirkevold, O. and Engedal, K. (2008). The course of psychiatric and behavioral symptoms and the use of psychotropic medication in patients with dementia in Norwegian nursing homes – a 12-month follow-up study. American Journal of Geriatric Psychiatry, 16, 528–536.CrossRefGoogle Scholar
Sink, K. M., Holden, K. F. and Yaffe, K. (2005). Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. Journal of the American Medical Association, 293, 596–608.CrossRefGoogle Scholar
Snowden, M., Sato, K. and Roy-Byrne, P. (2003 ). Assessment and treatment of nursing home residents with depression or behavioral symptoms associated with dementia: a review of the literature. Journal of the American Geriatrics Society, 51, 1305–1317.CrossRefGoogle ScholarPubMed
Snowdon, J., Galanos, D. and Vaswani, D. (2011). Patterns of psychotropic medication use in nursing homes: surveys in Sydney, allowing comparisons over time and between countries. International Psychogeriatrics.CrossRefGoogle Scholar
Sommer, O. H., Aga, O., Cvancarova, M., Olsen, I. C., Selbaek, G. and Engedal, K. (2009). Effect of oxcarbazepine in the treatment of agitation and aggression in severe dementia. Dementia and Geriatric Cognitive Disorders, 27, 155–163.CrossRefGoogle Scholar
Street, J. S.et al. (2000). Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. Archives of General Psychiatry, 57, 968–976.CrossRefGoogle Scholar
Streim, J. E.et al. (2008). A randomized, double-blind, placebo-controlled study of aripiprazole for the treatment of psychosis in nursing home patients with Alzheimer disease. American Journal of Geriatric Psychiatry, 16, 537–550.CrossRefGoogle Scholar
Sultzer, D. L.et al. (2008). Clinical symptom responses to atypical antipsychotic medications in Alzheimer's disease: phase 1 outcomes from the CATIE-AD effectiveness trial. American Journal of Psychiatry, 165, 844–854.CrossRefGoogle Scholar
Sutor, B., Rummans, T. A. and Smith, G. E. (2001). Assessment and management of behavioral disturbances in nursing home patients with dementia. Mayo Clinic Proceedings, 76, 540–550.CrossRefGoogle Scholar
Takkouche, B., Montes-Martinez, A., Gill, S. S. and Etminan, M. (2007). Psychotropic medications and the risk of fracture: a meta-analysis. Drug Safety, 30, 171–184.CrossRefGoogle Scholar
Tariot, P. N.et al. (1998 ). Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. American Journal of Psychiatry, 155, 54–61.CrossRefGoogle Scholar
Tariot, P. N.et al. (2001). A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting. Journal of the American Geriatrics Society, 49, 1590–1599.Google Scholar
Tariot, P. N.et al. (2005). Divalproex sodium in nursing home residents with possible or probable Alzheimer disease complicated by agitation: a randomized, controlled trial. American Journal of Geriatric Psychiatry, 13, 942–949.Google Scholar
Tariot, P. N.et al. (2006). Quetiapine treatment of psychosis associated with dementia: a double-blind, randomized, placebo-controlled clinical trial. American Journal of Geriatric Psychiatry, 14, 767–776 [Erratum: (2006). American Journal of Geriatric Psychiatry, 14, 988].CrossRefGoogle Scholar
Tariot, P. N.et al. (2011). Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Archives of General Psychiatry, 68, 853–861.CrossRefGoogle Scholar
Trifiro, G., Dieleman, J., Sen, E. F., Gambassi, G. and Sturkenboom, M. C. (2010). Risk of ischemic stroke associated with antidepressant drug use in elderly persons. Journal of Clinical Psychopharmacology, 30, 252–258.CrossRefGoogle Scholar
Turner, E. H., Matthews, A. M., Linardatos, E., Tell, R. A. and Rosenthal, R. (2008). Selective publication of antidepressant trials and its influence on apparent efficacy. New England Journal of Medicine, 358, 252–260.CrossRefGoogle Scholar
Van Reekum, R., Clarke, D., Conn, D., Hermann, N., Eryavec, G., Cohen, T. and Ostrander, L. (2002). A randomized, placebo-controlled trial of the discontinuation of long-term antipsychotics in dementia. International Psychogeriatrics, 14, 197–210.CrossRefGoogle ScholarPubMed
Verhey, F. R. J., Verkaaik, M. and Lousberg, R. (2006). Olanzapine versus haloperidol in the treatment of agitation in elderly patients with dementia: results of a randomized controlled double-blind trial. Dementia and Geriatric Cognitive Disorders, 21, 1–8.CrossRefGoogle Scholar
Vestergaard, P., Rejnmark, L. and Mosekilde, L. (2006). Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture. Osteoporosis International, 17, 807–816.CrossRefGoogle Scholar
Vigen, C. L.et al. (2011). Cognitive effects of atypical antipsychotic medications in patients with Alzheimer's disease: outcomes from CATIE-AD. American Journal of Psychiatry, 168, 831–839.CrossRefGoogle Scholar
Wang, P. S.et al. (2005). Risk of death in elderly users of conventional vs. atypical antipsychotic medications. New England Journal of Medicine, 353, 2335–2341.CrossRefGoogle Scholar
Wang, L. Y.et al. (2009). Prazosin for the treatment of behavioral symptoms in patients with Alzheimer disease with agitation and aggression. American Journal of Geriatric Psychiatry, 17, 744–751.CrossRefGoogle Scholar
Wu, C. S., Wang, S. C., Cheng, Y. C. and Gau, S. S. (2011). Association of cerebrovascular events with antidepressant use: a case-crossover study. American Journal of Psychiatry, 168, 511–521.CrossRefGoogle Scholar
Zhong, K. X., Tariot, P. N., Mintzer, J., Minkwitz, M. C. and Devine, N. A. (2007). Quetiapine to treat agitation in dementia: a randomized, double-blind, placebo-controlled study. Current Alzheimer Research, 4, 81–93.CrossRefGoogle Scholar
Zuidema, S., Koopmans, R. and Verhey, F. (2007). Prevalence and predictors of neuropsychiatric symptoms in cognitively impaired nursing home patients. Journal of Geriatric Psychiatry and Neurology, 20, 41–49.CrossRefGoogle Scholar
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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