RESEARCH Open Access

Efficacy and safety of atypical antipsychotic drugtreatment for dementia: a systematic review andmeta-analysisLin Tan1, Lan Tan1,2,3*, Hui-Fu Wang3, Jun Wang2, Chen-Chen Tan2, Meng-Shan Tan1, Xiang-Fei Meng2,Chong Wang2 and Jin-Tai Yu1,2,3*

Abstract

Introduction: A wide variety of atypical antipsychotic drugs (risperidone, olanzapine, quetiapine, aripiprazole,ziprasidone and clozapine) are widely used in the management of neuropsychiatric symptoms, which arecommonly seen in dementia, but results from randomised controlled trials (RCTs) on the efficacy and safety ofthese agents are conflicting. We aimed to quantify the efficacy and safety of atypical antipsychotic drugs onneuropsychiatric symptoms in dementia patients.

Methods: PubMed, EMBASE, the Cochrane Controlled Trials Register and the Cochrane Database of SystematicReviews for reports published before August 2014 were searched for eligible randomized controlled trials of atypicalantipsychotic drugs therapy in patients with psychotic symptoms of dementia. Two reviewers independentlyassessed the quality of the trials and extracted information.

Results: Overall, 23 relevant RCTs with 5,819 participants were identified. This meta-analysis demonstrated asignificant efficacy of atypical antipsychotics on psychiatric symptoms and cognitive functions compared toplacebo. In the meta-analysis, the weighted mean differences (WMDs) in change scores for psychiatric symptomswere in favor of aripiprazole (−4.4, 95% confidence interval (CI) – 7.04 to −1.77) and risperidone (−1.48, 95% CI −2.35to −0.61) compared to placebo. In cognitive effects, WMDs in change scores for the Clinical Global Impression-Change(CGI-C) were in favor of aripiprazole, risperidone, olanzapine and quetiapine which ranged from a −0.30 points meandifference (95% CI:-0.59 to −0.01) in the aripiprazole trials to −0.43 (95% CI:-0.62 to −0.25) in the risperidone group.Patients receiving atypical antipsychotics showed no difference in risk for injuries or falls (P > 0.05), significantly higherrisks (P < 0.05) for somnolence, urinary tract infection, edema and abnormal gait. However, there was no significantevidence for death reported.

Conclusion: Aripiprazole and risperidone are able to improve psychiatric symptoms and slow decline in cognitionfunction at average 12 weeks in patients with neuropsychiatric symptoms of dementia. However, high adverse eventsmay offset the efficacy of atypical antipsychotics in dementia.

IntroductionThe global prevalence of dementia is as high as 24 millioncases worldwide and has been predicted to quadruple bythe year 2050. Dementia causes unestimated healthcarecosts per year [1]. Neuropsychiatric symptoms rather thancognitive dysfunction or functional impairment have been

suggested to impose the greatest burden on family care-givers, and to predict caregivers’ decisions to institutio-nalize patients with dementia. Interventions targetingimproving neuropsychiatric symptoms could thereforehave a tremendous impact on patients, caregivers andsociety. There are multiple classes of pharmacologicalagents in use for neuropsychiatric symptoms, especiallyantipsychotics. The typical antipsychotic medications(for example, haloperidol or thioridazine), with or withoutpsychosocial and environmental interventions, are fre-quently used to treat symptoms that occur in a majority of

* Correspondence: dr.tanlan@163.com; yu-jintai@163.com1College of Medicine and Pharmaceutics, Ocean University of China, Qingdao266000, ChinaFull list of author information is available at the end of the article

© 2015 Tan et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,unless otherwise stated.

Tan et al. Alzheimer's Research & Therapy (2015) 7:20 DOI 10.1186/s13195-015-0102-9

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LEtreatment for dementia: a systematic review and

, Xiang-Fei Meng

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LE, Xiang-Fei Meng2

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A wide variety of atypical antipsychotic drugs (risperidone, olanzapine, quetiapine, aripiprazole,

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LEA wide variety of atypical antipsychotic drugs (risperidone, olanzapine, quetiapine, aripiprazole,

ziprasidone and clozapine) are widely used in the management of neuropsychiatric symptoms, which are

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ziprasidone and clozapine) are widely used in the management of neuropsychiatric symptoms, which arecommonly seen in dementia, but results from randomised controlled trials (RCTs) on the efficacy and safety of

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commonly seen in dementia, but results from randomised controlled trials (RCTs) on the efficacy and safety ofthese agents are conflicting. We aimed to quantify the efficacy and safety of atypical antipsychotic drugs on

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these agents are conflicting. We aimed to quantify the efficacy and safety of atypical antipsychotic drugs on

PubMed, EMBASE, the Cochrane Controlled Trials Register and the Cochrane Database of Systematic

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PubMed, EMBASE, the Cochrane Controlled Trials Register and the Cochrane Database of SystematicReviews for reports published before August 2014 were searched for eligible randomized controlled trials of atypical

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Reviews for reports published before August 2014 were searched for eligible randomized controlled trials of atypicalantipsychotic drugs therapy in patients with psychotic symptoms of dementia. Two reviewers independently

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antipsychotic drugs therapy in patients with psychotic symptoms of dementia. Two reviewers independentlyassessed the quality of the trials and extracted information.

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assessed the quality of the trials and extracted information.

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Overall, 23 relevant RCTs with 5,819 participants were identified. This meta-analysis demonstrated a

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Overall, 23 relevant RCTs with 5,819 participants were identified. This meta-analysis demonstrated asignificant efficacy of atypical antipsychotics on psychiatric symptoms and cognitive functions compared to

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significant efficacy of atypical antipsychotics on psychiatric symptoms and cognitive functions compared toplacebo. In the meta-analysis, the weighted mean differences (WMDs) in change scores for psychiatric symptoms

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placebo. In the meta-analysis, the weighted mean differences (WMDs) in change scores for psychiatric symptoms4.4, 95% confidence interval (CI)

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4.4, 95% confidence interval (CI)0.61) compared to placebo. In cognitive effects, WMDs in change scores for the Clinical Global Impression-Change

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0.61) compared to placebo. In cognitive effects, WMDs in change scores for the Clinical Global Impression-Change(CGI-C) were in favor of aripiprazole, risperidone, olanzapine and quetiapine which ranged from a

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(CGI-C) were in favor of aripiprazole, risperidone, olanzapine and quetiapine which ranged from a0.01) in the aripiprazole trials to

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0.01) in the aripiprazole trials toPatients receiving atypical antipsychotics showed no difference in risk for injuries or falls (

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Patients receiving atypical antipsychotics showed no difference in risk for injuries or falls (< 0.05) for somnolence, urinary tract infection, edema and abnormal gait. However, there was no significant

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< 0.05) for somnolence, urinary tract infection, edema and abnormal gait. However, there was no significantevidence for death reported.

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evidence for death reported.

Aripiprazole and risperidone are able to improve psychiatric symptoms and slow decline in cognition

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Aripiprazole and risperidone are able to improve psychiatric symptoms and slow decline in cognitionfunction at average 12 weeks in patients with neuropsychiatric symptoms of dementia. However, high adverse events

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function at average 12 weeks in patients with neuropsychiatric symptoms of dementia. However, high adverse eventsmay offset the efficacy of atypical antipsychotics in dementia.

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may offset the efficacy of atypical antipsychotics in dementia.

Introduction

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IntroductionThe global prevalence of dementia is as high as 24 million

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The global prevalence of dementia is as high as 24 millioncases worldwide and has been predicted to quadruple by

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cases worldwide and has been predicted to quadruple by

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the year 2050. Dementia causes unestimated healthcareRETRACTED ARTIC

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the year 2050. Dementia causes unestimated healthcarecosts per year [1]. Neuropsychiatric symptoms rather thanRETRACTED A

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costs per year [1]. Neuropsychiatric symptoms rather thanRETRACTED ARTIC

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cognitive dysfunction or functional impairment have beenRETRACTED ARTIC

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cognitive dysfunction or functional impairment have been

older patients with dementia during their illness courses,and have been the mainstay of psychopharmacologictreatment during the last several decades [2]. Interestingly,the atypical antipsychotics (that is, risperidone, olanza-pine, quetiapine, aripiprazole, ziprasidone and clozapine)generally have replaced conventional antipsychotics [3].Atypical antipsychotics are approved for marketing and la-beling by the US Food and Drug Administration for treat-ing schizophrenia, bipolar disorder and depression underdrug-specific circumstances [4]. To date, the use of atyp-ical antipsychotic medications is rapidly increasing in theUSA. They have been considered the preferred pharmaco-logic treatment for behavioral disturbances associated withdementia because evidence from clinical trials perceivedsafety advantages compared with other medications andexpert clinical opinion [5].The role of currently available atypical antipsychotics

for dementia has been controversial, however, with somenational formularies restricting their use and health eco-nomists questioning whether the small clinical effectsare economically worthwhile. Moreover, the efficacy ofziprasidone and clozapine in the treatment of dementiahas also been heavily debated. In addition, high dropoutrates and numerous adverse events have been observedin randomized clinical trials of these agents. Besides,safety concerns have been raised about the atypical anti-psychotics. Some clinical trials and meta-analyses haveevaluated the efficacy and safety of these drugs on neu-ropsychiatric symptoms, but have had conflicting find-ings [6]. We thus performed a systematic review andmeta-analysis to clarify the efficacy and safety of theseatypical antipsychotics for neuropsychiatric symptoms indementia patients. We sought to elaborate on previousreviews articles by including a broad spectrum of out-come measures, and to determine whether these drugshave different degrees of efficacy on psychiatric symp-toms and cognitive functions of dementia. Previous sys-tematic reviews or meta-analyses have been incompletein this regard.

MethodsSearch strategyThe search strategy was described in detail. Briefly, wesystematically searched PubMed, EMBASE, the CochraneControlled Trials Register and the Cochrane Database ofSystematic Reviews for reports published before August2014. The search criteria combined three separate do-mains: condition (dementia), intervention (risperidone,olanzapine, quetiapine, aripiprazole, ziprasidone, cloza-pine) and symptoms (behavioral and psychological symp-toms of dementia, BPSD, neuropsychiatric symptoms,behavior). We included studies reporting overall symp-toms of agitation, psychosis or aggression. Terms weresearched in titles and abstracts. We retrieved English-

language articles for review, and also collected additionalreferences from bibliographies of reviews, original re-search articles and other articles of interest. Pharmaceut-ical manufacturers were queried and information wasrequested as needed.Two investigators independently reviewed all pertinent

articles using predetermined inclusion criteria. Trialswere selected for inclusion if they met all of the fol-lowing criteria: parallel group, double-blind, placebo-controlled, randomized controlled trials (RCTs); patientshad psychiatric symptoms with Alzheimer’s disease (AD),vascular dementia, mixed dementia or a primary dementiaaccording to the Diagnostic and Statistical Manual ofMental Disorders – Fourth Edition [7]; and the number ofpatients randomized and at least one outcome measure oradverse event were obtainable.

Trials selectionWe selected double-blind, placebo-controlled RCTscomparing atypical antipsychotics with placebo that usedthe scales. Generally, trials of specific drugs used dif-ferent outcomes from trials of other drugs. The BriefPsychiatric Rating Scale (BPRS) [8] and the Neuro-psychiatric Inventory (NPI) [9] are used mainly for ari-piprazole trials, olanzapine trials, some quetiapine trialsand few risperidone trials. The Behavioral Pathology inAlzheimer’s Disease Rating Scale (BEHAVE-AD) [10] andthe Cohen-Mansfield Agitation Inventory (CMAI) [11]were generally used for risperidone trials. The ClinicalGlobal Impression – Change (CGI-C) and the ClinicalGlobal Impression – Severity (CGI-S) [12] were also usedas clinical outcomes in some trials. We used the NPI-totalscore, BPRS-total score and BEHAVE-AD score as thepsychiatric symptoms, while the CGI-C and MinimumMental State Examination (MMSE) were used as the cog-nitive functions. There is little clinical trial evidence forthe efficacy of ziprasidone and clozapine [6].

Data retrievalInformation extracted included design characteristics,selection criteria (dementia diagnoses and presence ofpsychosis of dementia), medication doses, trial durations(6 to 26 weeks), age, race, gender, baseline cognitivescores, baseline neuropsychiatric symptoms and num-bers randomized. The minimum baseline score for theNPI-total and the BPRS-total was 20 while that for theBEHAVE-AD was 15. For each trial, two reviewers wereblinded to the authors and journal, and independentlyabstracted data. The mean change of scale scores andstandard deviations for the mean change were extracted.For standard deviations that were not reported directly,we sought them from the authors or calculated themfrom standard errors, confidence intervals (CIs) or P valuesthat relate to the difference between means in two groups

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articles using predetermined inclusion criteria. Trials

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LEarticles using predetermined inclusion criteria. Trialswere selected for inclusion if they met all of the fol-

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LEwere selected for inclusion if they met all of the fol-lowing criteria: parallel group, double-blind, placebo-

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LElowing criteria: parallel group, double-blind, placebo-controlled, randomized controlled trials (RCTs); patients

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in randomized clinical trials of these agents. Besides,

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in randomized clinical trials of these agents. Besides,safety concerns have been raised about the atypical anti-

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safety concerns have been raised about the atypical anti-psychotics. Some clinical trials and meta-analyses have

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psychotics. Some clinical trials and meta-analyses haveevaluated the efficacy and safety of these drugs on neu-

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evaluated the efficacy and safety of these drugs on neu-ropsychiatric symptoms, but have had conflicting find-

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ropsychiatric symptoms, but have had conflicting find-ings [6]. We thus performed a systematic review and

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ings [6]. We thus performed a systematic review andmeta-analysis to clarify the efficacy and safety of these

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meta-analysis to clarify the efficacy and safety of theseatypical antipsychotics for neuropsychiatric symptoms in

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atypical antipsychotics for neuropsychiatric symptoms indementia patients. We sought to elaborate on previous

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dementia patients. We sought to elaborate on previousreviews articles by including a broad spectrum of out-

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reviews articles by including a broad spectrum of out-come measures, and to determine whether these drugs

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come measures, and to determine whether these drugshave different degrees of efficacy on psychiatric symp-

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have different degrees of efficacy on psychiatric symp-toms and cognitive functions of dementia. Previous sys-

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toms and cognitive functions of dementia. Previous sys-tematic reviews or meta-analyses have been incomplete

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tematic reviews or meta-analyses have been incompletein this regard.

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in this regard.

Methods

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MethodsSearch strategy

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Search strategyThe search strategy was described in detail. Briefly, we

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The search strategy was described in detail. Briefly, wesystematically searched PubMed, EMBASE, the Cochrane

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systematically searched PubMed, EMBASE, the CochraneControlled Trials Register and the Cochrane Database ofRETRACTED A

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Controlled Trials Register and the Cochrane Database ofSystematic Reviews for reports published before AugustRETRACTED A

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Systematic Reviews for reports published before August2014. The search criteria combined three separate do-RETRACTED A

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2014. The search criteria combined three separate do-

vascular dementia, mixed dementia or a primary dementia

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Diagnostic and Statistical Manual of

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patients randomized and at least one outcome measure or

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We selected double-blind, placebo-controlled RCTs

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We selected double-blind, placebo-controlled RCTscomparing atypical antipsychotics with placebo that used

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comparing atypical antipsychotics with placebo that usedthe scales. Generally, trials of specific drugs used dif-

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the scales. Generally, trials of specific drugs used dif-ferent outcomes from trials of other drugs. The Brief

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ferent outcomes from trials of other drugs. The BriefPsychiatric Rating Scale (BPRS) [8] and the Neuro-

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Psychiatric Rating Scale (BPRS) [8] and the Neuro-psychiatric Inventory (NPI) [9] are used mainly for ari-

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psychiatric Inventory (NPI) [9] are used mainly for ari-piprazole trials, olanzapine trials, some quetiapine trials

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piprazole trials, olanzapine trials, some quetiapine trialsand few risperidone trials. The Behavioral Pathology in

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and few risperidone trials. The Behavioral Pathology inAlzheimer

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Alzheimerthe Cohen-Mansfield Agitation Inventory (CMAI) [11]

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the Cohen-Mansfield Agitation Inventory (CMAI) [11]

according to the Cochrane Handbook for Systematic Re-views of Interventions [13]. Studies were excluded if the meanchange of scale total scores were not available. Moreover, ifthere were duplicate publications from the same popula-tion, only one of the trials that reported the mean changeof scale total score and standard deviation was included;others were excluded. Outcomes and adverse events datawere from the intent-to-treat or last-observation-carried-forward samples. Discrepancies in the collected data werediscussed, and if consensus was not reached a third re-viewer was the final arbitrator.

Statistical analysisMeta-analyses were performed using Review ManagerV.5.2 software (Review Manager, Version 5.2, Copenhagen:The Nordic Cochrane Centre, The Cochrane Collabor-ation, Denmark). Combining the scales in an overall sum-mary estimate, we calculated weighted mean differences(WMDs) and 95% CIs for changes from baseline for con-tinuous data. For dichotomous dropouts and adverseevents, we conducted an analysis of the odds ratio (OR),absolute risk differences with 95% CI and P values to as-sess the safety of the study drug. A random-effects modelwas applied to assess the effect sizes for each treatment–placebo comparison in our study.Because there were few dose-ranging trials and sparse

outcomes for adverse events, and to avoid multiple com-parisons with the same placebo group, we combineddosage groups within each trial to make one contrastwith placebo according to the Cochrane Handbook forSystematic Reviews of Interventions. The degree of het-erogeneity was assessed by visual inspection, and by achi-square test combined with the I2 method. The I2

statistic approximates the proportion of total variationin the effect size estimates that is the result of hete-rogeneity rather than sampling error. Values of α errorP <0.20 and I2 > 50% were regarded as indicators of hete-rogeneity of outcomes.

ResultsCharacteristics of included trialsThe results of the search process are depicted in theflowchart (Figure 1). Of 886 articles identified, three aripi-prazole articles [14-16], five olanzapine articles [17-21],seven quetiapine articles [17,19,22-26] and eight risperi-done articles [17,19,20,27-31] met all review criteria. Allstudies were RCTs and were performed mainly in NorthAmerican and European countries. Baseline characteristicswere similar between intervention and placebo groups inall of the trials. The included studies were all randomizedparallel trials for which the duration was 6 to 26 weeks. Inall, 13 trials compared one fixed dose of medicine and pla-cebo, and five trials were dose ranging. Among thesedose-ranging studies, three used more than one dose

compared with a single placebo group. These trials in-cluded 3,927 patients in the medicine treatment groupand 1,892 participants in the placebo treatment group.The mean ages of patients in the medicine treatmentgroups ranged from 77.3 to 84.2 years. The mean baselineMMSE scores ranged from 4.8 to 15.7. Additional file 1presents characteristics of these studies and populationsin more detail.

Bias risk assessmentAlthough all included trials were randomized, doubleblinded and placebo controlled, specification of rando-mization and allocation concealment methods were differ-ent from each other. The randomization was conductedaccording to a computerized randomization scheduleamong nine trials, four reports specified the variedmethods of randomization and the other 14 reports didnot give detailed information although they involvednoted randomization. Besides, efficacy outcomes of alltrials were analyzed by intent-to-treat data with thelast-observation-carried-forward method for minimiz-ing effects of attrition bias. A funnel plot did not showevidence of selection bias with symmetry around themean overall effect.

Psychiatric symptomsFor psychiatric symptoms, 15 studies measured and re-ported the mean change in NPI-total score from baselineto end point for intervention compared with placebo:three studies on aripiprazole [14-16], five studies onolanzapine [17-21], two studies on quetiapine (50 mg)[17,19], three studies on quetiapine (100 mg) [22,23,25]and two studies on risperidone [17,19]. All of these studiesincluded participants with moderate to severe dementia.NPI-total scores were only significant for aripiprazole bymeta-analysis in the available data (−4.4, 95% CI = −7.04

Figure 1 Flowchart of randomized controlled trials includedand excluded in the meta-analysis. RCT, randomizedcontrolled trial.

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Because there were few dose-ranging trials and sparse

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Because there were few dose-ranging trials and sparseoutcomes for adverse events, and to avoid multiple com-

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outcomes for adverse events, and to avoid multiple com-parisons with the same placebo group, we combined

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parisons with the same placebo group, we combineddosage groups within each trial to make one contrast

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dosage groups within each trial to make one contrastCochrane Handbook for

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Cochrane Handbook for. The degree of het-

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. The degree of het-erogeneity was assessed by visual inspection, and by a

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erogeneity was assessed by visual inspection, and by achi-square test combined with the

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chi-square test combined with the I

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I2

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2I2I

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I2I method. The

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method. Thestatistic approximates the proportion of total variation

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statistic approximates the proportion of total variationin the effect size estimates that is the result of hete-

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in the effect size estimates that is the result of hete-rogeneity rather than sampling error. Values of

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rogeneity rather than sampling error. Values of> 50% were regarded as indicators of hete-

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> 50% were regarded as indicators of hete-rogeneity of outcomes.

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rogeneity of outcomes.

Characteristics of included trials

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Characteristics of included trialsThe results of the search process are depicted in the

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The results of the search process are depicted in theflowchart (Figure 1). Of 886 articles identified, three aripi-

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flowchart (Figure 1). Of 886 articles identified, three aripi-prazole articles [14-16], five olanzapine articles [17-21],

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prazole articles [14-16], five olanzapine articles [17-21],seven quetiapine articles [17,19,22-26] and eight risperi-RETRACTED A

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seven quetiapine articles [17,19,22-26] and eight risperi-done articles [17,19,20,27-31] met all review criteria. AllRETRACTED A

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done articles [17,19,20,27-31] met all review criteria. Allstudies were RCTs and were performed mainly in NorthRETRACTED A

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studies were RCTs and were performed mainly in North

compared with a single placebo group. These trials in-

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compared with a single placebo group. These trials in-cluded 3,927 patients in the medicine treatment group

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cluded 3,927 patients in the medicine treatment groupand 1,892 participants in the placebo treatment group.

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and 1,892 participants in the placebo treatment group.The mean ages of patients in the medicine treatment

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The mean ages of patients in the medicine treatmentgroups ranged from 77.3 to 84.2 years. The mean baseline

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groups ranged from 77.3 to 84.2 years. The mean baselineMMSE scores ranged from 4.8 to 15.7. Additional file 1

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MMSE scores ranged from 4.8 to 15.7. Additional file 1presents characteristics of these studies and populations

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presents characteristics of these studies and populationsin more detail.

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in more detail.

Bias risk assessment

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Bias risk assessment

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and excluded in the meta-analysis.

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to −1.77). In the quetiapine trials, the differences bymeta-analysis were −4.3 (95% CI = −8.81 to 0.21) for the50 mg daily group and −0.12 (95% CI = −1.74 to 1.50)for the 100 mg daily group. In addition, the differencebetween the olanzapine group and placebo was −2.61(95% CI = −5.23 to −0.00) (Figure 2). The pooled studyNPI-total score was −1.68, which was of great signifi-cance (P = 0.004). Fourteen trials used the BPRS-totalscore: three studies on aripiprazole [14-16], five studies onolanzapine [17-21], two studies on quetiapine (50 mg)[17,19], two studies on quetiapine (100 mg) [23,25] andtwo studies on risperidone [17,19]. The score was only

significant for aripiprazole by meta-analysis in the avail-able data (95% CI = −3.44 to −0.62). In the quetiapinetrials, the differences by meta-analysis were −1.82 (95%CI = −4.00 to 0.36) for the 50 mg daily group and −2.23(95% CI = −4.83 to 0.38) for the 100 mg daily group. Inaddition, the difference between the olanzapine group andplacebo was −0.60 (95% CI = −1.98 to 0.78) (Figure 3).Only four risperidone trials reported changes in theBEHAVE-AD score [27-30]. The BEHAVE-AD scoreswere significant for risperidone by meta-analysis in theavailable data. The WMDs by meta-analysis were −1.48(95% CI = −2.35 to −0.61) (Figure 4). Furthermore, the

Figure 2 Forest plot for efficacy of the Neuropsychiatric Inventory-total score on dementia patients in subgroup analyses. Data type,continuous; effect measure, weighted mean difference; analysis model, fixed effects; statistical method, inverse variance. CI, confidence interval;SD, standard deviation.

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1.98 to 0.78) (Figure 3).

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Only four risperidone trials reported changes in the

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LEOnly four risperidone trials reported changes in theBEHAVE-AD score [27-30]. The BEHAVE-AD scores

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0.61) (Figure 4). Furthermore, the

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Figure 3 Forest plot for efficacy of the Brief Psychiatric Rating Scale-total score on dementia patients in subgroup analyses. Data type,continuous; effect measure, weighted mean difference; analysis model, fixed effects; statistical method, inverse variance. CI, confidence interval;SD, standard deviation.

Figure 4 Forest plot for efficacy of the Behavioral Pathology in Alzheimer’s Disease Rating Scale score on dementia patients insubgroup analyses. Data type, continuous; effect measure, weighted mean difference; analysis model, fixed effects; statistical method, inversevariance. CI, confidence interval; SD, standard deviation.

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Forest plot for efficacy of the Brief Psychiatric Rating Scale-total score on dementia patients in subgroup analyses.

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effects with four drugs (risperidone, olanzapine, quetia-pine, aripiprazole) on specific psychosis subscales of theBPRS (see Additional file 2), NPI (see Additional file 3)or BEHAVE-AD (see Additional file 4) were analyzed.There were no significant effects by meta-analysis forthree aripiprazole trials, three olanzapine trials, one ris-peridone trial and one quetiapine trial on the NPI psy-chosis subscales (WMD= −0.42, 95% CI = −0.91 to 0.08,P = 0.29). However, aripiprazole trials alone showed a sig-nificant effect on NPI psychosis subscales (WMD= −0.88,95% CI = −1.61 to −0.16, P = 0.02). For aripiprazole, theBPRS psychosis subscale scores by meta-analysis werenot significant (WMD = −0.23, 95% CI = −0.60 to 0.08,P = 0.23). There was a significant effect by meta-analysiswith risperidone on the BEHAVE-AD psychosis subscalefrom four trials (WMD= −0.84, 95% CI = −1.24 to −0.44,

P <0.0001). The quality of reports for all included studieswas appraised with GRADE software (Grading of Recom-mendations Assessment, Development and Evaluation,Version 3.6, Hamilton, Canada), and the outcome ispresented in Additional files 5, 6 and 7.

Cognitive functionsThirteen studies measured and reported the mean changein CGI-C from baseline to end point for interventioncompared with placebo: one study on aripiprazole [15],three studies on olanzapine [17,19,21], five studies onquetiapine [19,22-25] and four studies on risperidone[17,19,27-30]. CGI-C scores were all significant for thesetrials by meta-analysis in the available data. The differencebetween the pooled group and placebo was −0.36 (95%CI = −0.47 to −0.25) (Figure 5). Furthermore, 13 trials

Figure 5 Forest plot for Clinical Global Impression – Change subscale scores on dementia patients in subgroup analyses. Data type,continuous; effect measure, weighted mean difference; analysis model, fixed effects; statistical method, inverse variance. CI, confidence interval;SD, standard deviation.

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0.25) (Figure 5). Furthermore, 13 trials

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reported MMSE change scores: three aripiprazole con-trasts [14-16], three olanzapine contrasts [17,18,20], tworisperidone contrasts [17,20] and five quetiapine contrasts[19,22-25]. The overall effect of drugs compared withplacebo was a WMD of −0.34 (95% CI = −0.65 to −0.03,P = 0.03) in favor of placebo. The three aripiprazole trialsshowed statistical significance of MMSE in favor of pla-cebo (WMD= −0.99, 95% CI = −1.65 to −0.33, P = 0.003)(Figure 6). The quality of reports for all included studieswas appraised with GRADE software. The outcome ispresented in Additional files 8 and 9.

General assessment of atypical antipsychotic drugsAripiprazoleThe three aripiprazole trials retrieved were designed simi-larly, with similar selection criteria – AD with psychosisand 10-week treatment durations – and the same primary

and secondary outcomes – that is, BPRS, NPI, CGI-S andCMAI. Two were nursing home trials and one was anoutpatient trial. One trial was a dose-ranging trial in-cluding 2, 5 and 10 mg/day [15]. Significant effects bymeta-analysis were observed on the BPRS-total andNPI-total change scores (WMD = −4.4, 95% CI = −7.04to −1.77, P= 0.001; WMD= −2.03, 95% CI = −3.44 to −0.62,P = 0.005). A significant effect by meta-analysis on theCMAI was observed but was based on only the two nurs-ing home trials (WMD= −4.73, 95% CI = −7.43 to −2.03,P = 0.0006). Global clinical ratings were reported only ascontinuous outcomes with a one-point to seven-pointrange and not as categorical or individual response-basedoutcomes. The CGI-S was significant in favor of aripi-prazole by meta-analysis (WMD = −0.16, 95% CI = −3.0to −0.03, P = 0.02). The heterogeneity among the studywas mild (I2 = 0%).

Figure 6 Forest plot for Minimum Mental State Examination in dementia patients. Data type, continuous; effect measure, weighted meandifference; analysis model, fixed effects; statistical method, inverse variance. CI, confidence interval; SD, standard deviation.

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= 0.005). A significant effect by meta-analysis on the

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continuous outcomes with a one-point to seven-point

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OlanzapineAmong the five olanzapine trials, four trials retrievedwere designed with similar selection criteria – AD withpsychosis, 6-week to 12-week treatment durations – andthe same primary outcomes – that is, BPRS and NPI.Two were nursing home trials and three were out-patient trials. Three trials chose patients with psychoticand behavioral symptoms. Other two trials focused on pa-tients with psychosis, aggression or agitation. Two trialswere dose-ranging trials including 5, 10 and 15 mg/dayand 5 and 7.5 mg/day respectively. We only chose theaverage 5 mg/day group for meta-analysis.Among these five trials, there were nonsignificant effects

by meta-analysis on the BPRS and NPI (WMD= −0.6,95% CI = −1.98 to 0.78, P = 0.40; WMD = −2.61, 95%CI = −5.23 to 0.00, P = 0.05;respectively).

QuetiapineThe designs, selection criteria and outcomes scales dif-fered substantially among the seven quetiapine trials andwe combined the same dose group for efficacy out-comes. One study enrolled primarily nursing home pa-tients with psychosis in patients with probable/possibleAD and assessed other psychopathology and social anddaily functioning [23]. Four trials chose patients with aprimary dementia, AD, vascular dementia or mixed de-mentia, mainly manifesting agitation severe enough to re-quire an antipsychotic. Among the four trials, a smallertrial chose nursing home patients with AD and agitationand compared quetiapine treatment with rivastigmineand placebo [26]. The other two trials focused on thebehavioral and psychological symptoms of dementiapatients [17,24].Two trials showed no significant effect for the 50 mg/

day quetiapine treatment groups on the BPRS and NPI(WMD = −1.82, 95% CI = −4.00 to 0.36, P = 0.10;WMD = −4.3, 95% CI = −8.81 to 0.21, P = 0.06; respect-ively). Three trials showed no statistically significanteffect for the 100 mg/day quetiapine treatment groups

on the BPRS and NPI (WMD = −0.12, 95% CI = −1.74to 1.50, P = 0.89; WMD = −2.23, 95% CI = −4.83 to0.38, P = 0.09; respectively).

RisperidoneAmong the eight risperidone trials, four were similarlydesigned in that they selected nursing home patientswith dementia and aggression, had a minimum score onthe BEHAVE-AD of ≥8 and were treated for an average12 weeks. Three trials enrolled AD patients with psy-chotic and behavioral symptoms. Schneider and col-leagues’ trial selected patients with psychosis. Theseeight trials used similar primary efficacy outcomes; thatis, the BEHAVE-AD and CMAI. The CGI-C, CGI-S,NPI and BPRS were also used as secondary outcomesin some trials.Among the four trials using the BEHAVE-AD, there

was overall significant improvement with risperidone(WMD = −1.48, 95% CI = −2.35 to −0.61, P = 0.0008) andon the CMAI used in three trials (WMD = −3.00, 95%CI = −4.22 to −1.78, P <0.00001). There was a statisticallysignificant effect overall by meta-analysis on the CGI-S intwo trials as a continuous variable (WMD= −0.39, 95%CI = −0.58 to −0.20, P <0.0001). However, no significantdifference was observed for the NPI or BPRS score.

SafetyAdverse eventsAdverse events were inconsistently reported among thetrials; most did not report adverse events occurring lessthan 20% of the time, and potentially significant adverseevents could not be counted from all trials. Somnolence,falls, injury, edema and urinary tract infections weremostly reported from the trials. Adverse events are sum-marized by the numbers of trials for which the eventwas reported and the odds ratio for the event (Table 1).The quality of reports of all included studies was ap-praised with GRADE software, and the outcome is pre-sented in Additional file 10.

Table 1 Odds ratios by meta-analysis of adverse effects in atypical antipsychotics compared with placebo

Somnolence Injuries or falls Abnormal gait Edema Urinary infection Stroke

Aripiprazole OR 3.51 0.86 5.04 0.93 1.20 1.58

(95% CI) (1.64, 7.5) (0.58, 1.28) (0.58, 43.81) (0.38, 2.27) (0.78, 1.87) (0.38, 6.55)

Olanzapine OR 3.61 1.13 3.84 0.52 6.93 3.93

(95% CI) (1.83, 7.13) (0.72, 1.76) (1.64, 8.95) (0.16, 1.69) (1.33, 35.96) (0.62, 25.10)

Risperidone OR 3.57 0.85 1.21 0.49 2.28 4.53

(95% CI) (2.72, 4.67) (0.68, 1.08) (0.73, 1.99) (0.30, 0.78) (1.58,3.30) (1.75, 11.72)

Quetiapine OR 5.88 0.86 1.98 1.51 1.90 1.13

(95% CI) (2.39, 14.47) (0.57, 1.29) (0.73, 5.39) (0.55, 4.19) (0.95, 3.8) (0.36, 3.56)

CI, confidence interval; OR, odds ratio.

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eight trials used similar primary efficacy outcomes; that

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AD and assessed other psychopathology and social anddaily functioning [23]. Four trials chose patients with a

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mentia, mainly manifesting agitation severe enough to re-quire an antipsychotic. Among the four trials, a smaller

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trial chose nursing home patients with AD and agitationand compared quetiapine treatment with rivastigmine

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and compared quetiapine treatment with rivastigmineand placebo [26]. The other two trials focused on the

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and placebo [26]. The other two trials focused on thebehavioral and psychological symptoms of dementia

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behavioral and psychological symptoms of dementia

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day quetiapine treatment groups on the BPRS and NPI1.82, 95% CI =

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Table 1 Odds ratios by meta-analysis of adverse effects in atypical antipsychotics compared with placebo

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Table 1 Odds ratios by meta-analysis of adverse effects in atypical antipsychotics compared with placebo

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Aripiprazole OR 3.51 0.86 5.04 0.93 1.20 1.58

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Olanzapine OR 3.61 1.13 3.84 0.52 6.93 3.93

SomnolenceThe 13 available comparisons all showed increased riskfor somnolence, and all of them were statistically sig-nificant. The odds ratio by meta-analysis was 3.7 (95%CI = 2.94 to 4.66, P <0.00001) with significant hetero-geneity. Significant risk differences were found amongaripiprazole (OR = 3.51, 95% CI = 1.64 to 7.50), olanza-pine (OR = 3.61, 95% CI = 1.83 to 7.13) and quetiapine(OR = 5.88, 95% CI = 2.39 to 14.47) with small hetero-geneity (I2 = 0%).

Injury or fallsOutcomes are consistent in the 15 contrasts that pro-vided data for injury/accidental injury and falls. They didnot show an increase or decrease in risk overall or in theresult of a particular drug or trial (OR = 0.89, 95% CI =0.75 to 1.05, P = 0.17).

Abnormal gaitThere was an overall increased risk for abnormal gait inthe pooled analysis (OR = 1.84, 95% CI = 1.26 to 2.68,P = 0.002) from 10 trials. There was increased risk inthree olanzapine trials, and no increased risk in one ari-piprazole trial, three risperidone trials and three quetia-pine trials.

EdemaNine trials reported edema. Increased risks was observedby meta-analysis for edema (OR = 0.63, 95% CI = 0.44 to0.91, P = 0.01). The increased risk was associated withrisperidone. Two of three aripiprazole trials, three of fiveolanzapine trials, four of eight risperidone trials and fiveof seven quetiapine trials did not report edema.

Urinary tract infectionsUrinary tract infections were reported in 11 contrasts,including three aripiprazole trials, two olanzapine trials,four risperidone trials and two quetiapine trials. Therewas overall increased risk for urinary tract infections inthe antipsychotic-treated patients (OR = 1.91, 95% CI =1.48 to 2.46, P <0.00001). The effect was not significantwith aripiprazole and quetiapine, but was significantwhen the events were combined. Urinary tract infectionswere not reported in one olanzapine trial (one trial in-cluded risperidone), but urinary incontinence both wasand was not reported in the trials of the other drugs.

StrokeStroke was reported in 13 contrasts including threearipiprazole trials, two olanzapine trials, four risperidonetrials and four quetiapine trials. There was overallincreased risk for stroke in the antipsychotic-treatedpatients. Meta-analysis demonstrated a significantlyhigher risk of stroke in the pooled antipsychotic group

(OR = 2.62, 95% CI = 1.45 to 4.75, P = 0.001) and in therisperidone subgroup (P = 0.002). However, the effectwas not significant with aripiprazole, olanzapine andquetiapine (see Additional file 11).

DeathsThe overall OR by meta-analysis for death in patientstreated with antipsychotics compared with placebo was1.06 (95% CI = 0.65 to 1.73; Z = 0.24, P = 0.81). Therewas no increased risk of death with any individual drug.Besides, in most studies, adverse reactions occurring inless than 20% of patients were not taken into accountwhen not finding a significantly higher prevalence ofmortality.

All-cause dropoutsIn overall meta-analyses on safety, there were no signifi-cant differences in the number of dropouts caused byany reason between any medicine treatment group andplacebo treatment group (OR = 0.95, 95% CI = 0.82 to1.09; Z = 0.75, P = 0.45). In subgroups, we observed simi-lar results (aripiprazole, 95% CI = 0.63 to 1.39; olanza-pine, 95% CI = 0.57 to 1.13; risperidone, 95% CI = 0.79 to1.22; quetiapine, 95% CI = 0.74 to 1.36) (see Additionalfile 12).

DiscussionPsychiatric symptoms occur on average in 70% of demen-tia patients during the primary illness [6]. The use ofatypical antipsychotic medications is therefore increas-ing rapidly. Atypical antipsychotics have been consid-ered preferred pharmacologic treatments for behavioraldisturbances associated with dementia because of clinicaltrial evidence for perceived safety advantages comparedwith other medications and expert clinical opinion. How-ever, the role of currently available atypical antipsychoticsfor dementia has been controversial and health econo-mists always question whether the small clinical effectsare economically worthwhile. In our present study, wehave obtained the treatment effects of 23 trials including5,819 patients with dementia. Our results show obviousbenefits for symptomatic efficacy on psychiatric symptomsand cognitive functions of aripiprazole and risperidoneafter statistically combining the trials. The safety of atyp-ical antipsychotics may offset the usage of drugs.A previous study by Schneider and colleagues analyzed

15 RCTs (from published articles or presentations atmedical meetings) of three aripiprazole trials, five olan-zapine trials, three quetiapine trials and four risperidoneand found modest benefits for aripiprazole and risperi-done, but also that adverse events and dropouts blockedtheir efficacy [32]. Furthermore, Maher and colleaguesconducted a meta-analysis on efficacy and comparativeeffectiveness of atypical antipsychotics for off-label uses

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In overall meta-analyses on safety, there were no signifi-

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cant differences in the number of dropouts caused byany reason between any medicine treatment group and

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any reason between any medicine treatment group andplacebo treatment group (OR = 0.95, 95% CI = 0.82 to

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placebo treatment group (OR = 0.95, 95% CI = 0.82 toZ

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Z

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Nine trials reported edema. Increased risks was observed

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Nine trials reported edema. Increased risks was observedby meta-analysis for edema (OR = 0.63, 95% CI = 0.44 to

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by meta-analysis for edema (OR = 0.63, 95% CI = 0.44 to= 0.01). The increased risk was associated with

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= 0.01). The increased risk was associated withrisperidone. Two of three aripiprazole trials, three of five

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risperidone. Two of three aripiprazole trials, three of fiveolanzapine trials, four of eight risperidone trials and five

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olanzapine trials, four of eight risperidone trials and fiveof seven quetiapine trials did not report edema.

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of seven quetiapine trials did not report edema.

Urinary tract infections were reported in 11 contrasts,

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Urinary tract infections were reported in 11 contrasts,including three aripiprazole trials, two olanzapine trials,

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including three aripiprazole trials, two olanzapine trials,four risperidone trials and two quetiapine trials. There

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four risperidone trials and two quetiapine trials. Therewas overall increased risk for urinary tract infections in

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was overall increased risk for urinary tract infections inthe antipsychotic-treated patients (OR = 1.91, 95% CI =

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the antipsychotic-treated patients (OR = 1.91, 95% CI =1.48 to 2.46,

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1.48 to 2.46, P

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P <0.00001). The effect was not significant

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<0.00001). The effect was not significantwith aripiprazole and quetiapine, but was significant

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with aripiprazole and quetiapine, but was significantwhen the events were combined. Urinary tract infections

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when the events were combined. Urinary tract infectionswere not reported in one olanzapine trial (one trial in-

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were not reported in one olanzapine trial (one trial in-cluded risperidone), but urinary incontinence both wasRETRACTED A

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= 0.75,

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= 0.45). In subgroups, we observed simi-lar results (aripiprazole, 95% CI = 0.63 to 1.39; olanza-

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lar results (aripiprazole, 95% CI = 0.63 to 1.39; olanza-pine, 95% CI = 0.57 to 1.13; risperidone, 95% CI = 0.79 to

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pine, 95% CI = 0.57 to 1.13; risperidone, 95% CI = 0.79 to1.22; quetiapine, 95% CI = 0.74 to 1.36) (see Additional

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1.22; quetiapine, 95% CI = 0.74 to 1.36) (see Additionalfile 12).

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file 12).

Discussion

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DiscussionPsychiatric symptoms occur on average in 70% of demen-

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Psychiatric symptoms occur on average in 70% of demen-

in psychosis, agitation and global behavioral symptomsin dementia. They found small but statistically signifi-cant pooled effect size for aripiprazole, olanzapine andrisperidone [33]. A previous paper indicated that aripi-prazole shows modest efficacy in the treatment of AD-related psychosis [34]. The benefit of aripiprazole indementia was consistent in the previous study and ourmeta-analysis. However, olanzapine was not associatedwith efficacy overall in our study. Besides, there was alack of evidence for or against quetiapine because fiveamong the seven trials were dose-ranging and used dif-ferent selection criteria. The outcomes could not bestatistically combined using a common rating scale.Furthermore, Katz and colleagues found that risperi-done showed improvement in psychotic symptoms andgeneral clinical improvement in patients with psychosisof AD [28]. However, in our study, risperidone showedimprovement in behavior symptoms on dementia. Inaddition, aripiprazole, olanzapine and quetiapine weremore effective for particular symptoms, such as angerand aggression. They all proved to have significant ef-fect on neuropsychiatric symptoms in early studies. Asa result, our study is in line with findings from a formerreview [32] and long-standing clinical experience.The duration of RCTs of atypical antipsychotics varies

from 6 to 26 weeks. Because the length of treatment aswell as methodological factors may be stronger outcomemodifiers, a considerable number of placebo-controlledRCTs of atypical antipsychotics for stabilizing or slowingdecline in psychiatric symptoms and cognitive functionsof patients with dementia have been undertaken for gen-erally 6 to 12 weeks in this study. The possible methodo-logical factors that may be relevant as strong outcomemodifiers are publication bias or different randomizationmethods. We only focused on published English-languagestudies and there are additional unpublished studies thathave been identified, which may have introduced a pub-lication bias in favor of studies showing benefits withmedications [32]. In addition, although the studies in-cluded were randomized, they may not apply the samerandomization method.Safety is as important as the efficacy of the interven-

tions in clinical studies. The five main adverse eventswere analyzed here and the pooled study showed evidencein increasing somnolence, edema, urinary infection andabnormal gait. Patients receiving atypical antipsychoticsshowed no difference in risk for injuries or falls (P >0.05),and significantly higher risks (P <0.05) for somnolence,urinary tract infection or urinary incontinence, edema andabnormal gait. Notably, risperidone had a higher risk onadverse events. However, no drugs improved or aggra-vated injuries or falls compared with placebos. Theseevents were usually of mild or moderate severity, and therisk disappeared on serious adverse events. Finally, none

of these drugs seemed to increase the risk of death in thisstudy, yet the difference did not achieve statistically sig-nificant levels. Similarly, Schneider and colleagues found asignificant risk for somnolence, abnormal gait, edema,urinary tract infection or urinary incontinence on atypicalantipsychotics versus placebo [32]. In general, the resultsof our meta-analysis demonstrated statistical increasedrisks of 1.1-fold to 1.5-fold for these adverse events. Thus,an increased risk of AEs in atypical antipsychotics is ob-served during these years. Importantly, a follow-up studyindicated that there was an increased long-term risk ofmortality in patients with AD who are prescribed anti-psychotic medication [35]. These results further supportedthe need to seek less harmful alternatives for the long-term treatment of neuropsychiatric symptoms in dementiapatients.Although previous systematic reviews or meta-analysis

have been reported, atypical antipsychotics producedmodest benefits on neuropsychiatric outcomes. To date,we perform a more comprehensive analysis covering avariety of outcome domains that included many previousstudies without a higher risk of bias. Besides, we identi-fied and included five recent studies to conduct an up-dated meta-analysis, and our results further supportedthis. There was some evidence to support the efficacy ofthe atypical antipsychotics when compared with placeboon change in neuropsychiatric symptom scores in theprevious reviews [36,37]. These trials offered updatedinformation of atypical antipsychotics in psychiatricsymptoms and cognitive functions, which may havecontributed to the differences between our review andprevious reviews. More importantly, compared with theprevious reviews, our study added quality assessmentanalysis. Quality assessment by GRADE software wasused to establish the robustness of the primary out-come, and higher robustness means study drugs havemore definite effects on the diseases. Because the mag-nitude of statistical effect does not always imply a similarmagnitude clinical effect, we also reviewed and analyzedeach drug separately and by specific outcomes to betteraddress the psychiatric symptoms (see Additional files 13,14, 15 and 16).Several limitations to our meta-analysis restrict the in-

terpretation of our results. First, some of our includedtrials excluded participants receiving psychotropic medi-cines, while some trials allowed, and even demanded,the use of medicines such as cholinesterase inhibitorsand other drugs in their study. The use of such medicinesmay have an impact on our results. In addition, dementiais progressive and patients declined at progressive differ-ent stages of severity, which may also influence our resultswhen pooling data. Finally, there still were very limitedtrials per each study drug and dose in this present study;unfortunately, some items tested in the trials were not

Tan et al. Alzheimer's Research & Therapy (2015) 7:20 Page 10 of 13

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LEantipsychotics versus placebo [32]. In general, the results

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LEantipsychotics versus placebo [32]. In general, the resultsof our meta-analysis demonstrated statistical increased

RETRACTED ARTIC

LEof our meta-analysis demonstrated statistical increasedrisks of 1.1-fold to 1.5-fold for these adverse events. Thus,

RETRACTED ARTIC

LErisks of 1.1-fold to 1.5-fold for these adverse events. Thus,an increased risk of AEs in atypical antipsychotics is ob-

RETRACTED ARTIC

LEan increased risk of AEs in atypical antipsychotics is ob-served during these years. Importantly, a follow-up study

RETRACTED ARTIC

LEserved during these years. Importantly, a follow-up studyindicated that there was an increased long-term risk of

RETRACTED ARTIC

LEindicated that there was an increased long-term risk ofmortality in patients with AD who are prescribed anti-

RETRACTED ARTIC

LEmortality in patients with AD who are prescribed anti-psychotic medication [35]. These results further supported

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LEpsychotic medication [35]. These results further supportedthe need to seek less harmful alternatives for the long-

RETRACTED ARTIC

LEthe need to seek less harmful alternatives for the long-

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LE

The duration of RCTs of atypical antipsychotics varies

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The duration of RCTs of atypical antipsychotics variesfrom 6 to 26 weeks. Because the length of treatment as

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from 6 to 26 weeks. Because the length of treatment aswell as methodological factors may be stronger outcome

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well as methodological factors may be stronger outcomemodifiers, a considerable number of placebo-controlled

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modifiers, a considerable number of placebo-controlledRCTs of atypical antipsychotics for stabilizing or slowing

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RCTs of atypical antipsychotics for stabilizing or slowingdecline in psychiatric symptoms and cognitive functions

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decline in psychiatric symptoms and cognitive functionsof patients with dementia have been undertaken for gen-

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of patients with dementia have been undertaken for gen-erally 6 to 12 weeks in this study. The possible methodo-

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erally 6 to 12 weeks in this study. The possible methodo-logical factors that may be relevant as strong outcome

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logical factors that may be relevant as strong outcomemodifiers are publication bias or different randomization

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modifiers are publication bias or different randomizationmethods. We only focused on published English-language

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methods. We only focused on published English-languagestudies and there are additional unpublished studies that

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studies and there are additional unpublished studies thathave been identified, which may have introduced a pub-

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have been identified, which may have introduced a pub-lication bias in favor of studies showing benefits with

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lication bias in favor of studies showing benefits withmedications [32]. In addition, although the studies in-

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medications [32]. In addition, although the studies in-cluded were randomized, they may not apply the same

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cluded were randomized, they may not apply the samerandomization method.

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randomization method.Safety is as important as the efficacy of the interven-

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Safety is as important as the efficacy of the interven-tions in clinical studies. The five main adverse events

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tions in clinical studies. The five main adverse eventswere analyzed here and the pooled study showed evidence

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were analyzed here and the pooled study showed evidencein increasing somnolence, edema, urinary infection andRETRACTED A

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in increasing somnolence, edema, urinary infection andabnormal gait. Patients receiving atypical antipsychoticsRETRACTED A

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abnormal gait. Patients receiving atypical antipsychoticsshowed no difference in risk for injuries or falls (RETRACTED A

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showed no difference in risk for injuries or falls (

term treatment of neuropsychiatric symptoms in dementia

RETRACTED ARTIC

LEterm treatment of neuropsychiatric symptoms in dementia

Although previous systematic reviews or meta-analysis

RETRACTED ARTIC

LEAlthough previous systematic reviews or meta-analysis

have been reported, atypical antipsychotics produced

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LE

have been reported, atypical antipsychotics producedmodest benefits on neuropsychiatric outcomes. To date,

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modest benefits on neuropsychiatric outcomes. To date,we perform a more comprehensive analysis covering a

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LE

we perform a more comprehensive analysis covering avariety of outcome domains that included many previous

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LE

variety of outcome domains that included many previousstudies without a higher risk of bias. Besides, we identi-

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studies without a higher risk of bias. Besides, we identi-fied and included five recent studies to conduct an up-

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LE

fied and included five recent studies to conduct an up-dated meta-analysis, and our results further supported

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dated meta-analysis, and our results further supportedthis. There was some evidence to support the efficacy of

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this. There was some evidence to support the efficacy ofthe atypical antipsychotics when compared with placebo

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LE

the atypical antipsychotics when compared with placeboon change in neuropsychiatric symptom scores in the

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on change in neuropsychiatric symptom scores in theprevious reviews [36,37]. These trials offered updated

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previous reviews [36,37]. These trials offered updated

available in the results, and despite numerous attempts tocontact the authors, further details were still absent. Inaddition, we must note that despite differences in out-come measures such as the NPI and so forth, the outcomesymptoms may also differ among studies (such as agita-tion and/of psychosis). Therefore, no convincing conclu-sions can be drawn regarding the efficacy of these drugsfor neuropsychiatric symptoms. Furthermore, some trialsfound no significant differences in outcomes betweenthe withdrawal of the drugs and continuation groups.Decision-making related to antipsychotic drug treatmentin dementia remains challenging and requires a thoughtfulapproach [38]. What is worth noting is that the heterogen-eity was substantial for the outcomes. We detected a sub-stantial heterogeneity in meta-analyses in NPI psychosisor BPRS psychosis. There are several interpretations forthe heterogeneity. First, it may indicate that many dif-ferences still exist between different kinds of dementia,although they are highly identical in clinical and neuro-pathological symptoms. The second sources of hetero-geneity may be the discrepancy in treatment durationand bias risk, and the diversity in concomitant patho-logic condition and drug therapy.Despite some limitations, we believe that our results

are the newest and most comprehensive attempt to quan-titatively synthesize the efficacy and safety of atypicalantipsychotics for neuropsychiatric symptoms of dementiapatients, suggesting a moderate benefit in neuropsychiatricoutcomes from antipsychotics. Our meta-analysis resultsindicate that for dementia patients who have neuropsychiatricdisturbances, atypical antipsychotics may be considered as atherapeutic option. However, it is notable that the decision touse these medicines needs to be considered in light of theadverse effects, cost and feasibility. As recommended, fordementia patients with neuropsychiatric symptoms, excludingmedical and environmental factors, drug therapy should beused to manage neuropsychiatric symptoms. Overall, ourmeta-analysis results indicate a benefit in neuropsychiatricsymptoms for dementia patients from atypical antipsychotics.

ConclusionObvious benefits were observed for symptomatic efficacyon psychiatric symptoms and cognitive functions of ari-piprazole and risperidone after statistically combiningthe trials. The higher risks for adverse events may offsetthe efficacy of atypical antipsychotics for treatment ofdementia. Hopefully, the design of a multicenter studycould use currently available levels of treatment andcare, in order to provide a broader generalizability of theresults in the future. Future research should focus moreon neuropsychiatric outcomes. It is important to continueefforts to perform high-quality trials of drug therapy, andthe safety evaluation of the drugs cannot be ignored.

Additional files

Additional file 1: Is a table presenting the basic information of allincluded studies.

Additional file 2: Is a forest plot of specific BPRS psychosissubscales on dementia patients in subgroup analyses. Data type,continuous; effect measure, weighted mean difference; analysis model,fixed effects; statistical method, inverse variance.

Additional file 3: Is a forest plot of specific NPI psychosis subscaleson dementia patients in subgroup analyses. Data type, continuous;effect measure, weighted mean difference; analysis model, fixed effects;statistical method, inverse variance.

Additional file 4: Is a forest plot of specific BEHAVE-AD psychosissubscales on dementia patients in subgroup analyses. Data type,continuous; effect measure, weighted mean difference; analysis model,fixed effects; statistical method, inverse variance.

Additional file 5: Is a table presenting the quality assessment onNPI of all included studies in dementia patients.

Additional file 6: Is a table presenting the quality assessment onBPRS of all included studies in dementia patients.

Additional file 7: Is a table presenting the quality assessment onBEHAVE-AD of all included studies in dementia patients.

Additional file 8: Is a table presenting the quality assessment onCGI-C of all included studies in dementia patients.

Additional file 9: Is a table presenting the quality assessment onMMSE of all included studies in dementia patients.

Additional file 10: Is a table presenting the quality assessment onadverse events of all included studies in dementia patients.

Additional file 11: Is a forest plot of stroke of four drugs onall-cause dropouts in dementia patients. Data type, dichotomous;effect measure, odds ratio; analysis model, fixed effects; statisticalmethod, Mantel–Haenszel.

Additional file 12: Is a forest plot of safety of four drugs onall-cause dropouts in dementia patients. Data type, dichotomous;effect measure, odds ratio; analysis model, fixed effects; statisticalmethod, Mantel–Haenszel.

Additional file 13: Is a forest plot of aripiprazole on dementiapatients in subgroup analyses. Data type, continuous; effect measure,weighted mean difference; analysis model, fixed effects; statisticalmethod, inverse variance.

Additional file 14: Is a forest plot of olanzapine on dementiapatients in subgroup analyses. Data type, continuous; effect measure,weighted mean difference; analysis model, fixed effects; statisticalmethod, inverse variance.

Additional file 15: Is a forest plot of quetiapine on dementiapatients in subgroup analyses. Data type, continuous; effect measure,weighted mean difference; analysis model, fixed effects; statisticalmethod, inverse variance.

Additional file 16: Is a forest plot of risperidone on dementiapatients in subgroup analyses. Data type, continuous; effect measure,weighted mean difference; analysis model, fixed effects; statisticalmethod, inverse variance.

AbbreviationsAD: Alzheimer’s disease; BEHAVE-AD: Behavioral Pathology in Alzheimer’sDisease Rating Scale; BPRS: Brief Psychiatric Rating Scale; CGI-C: ClinicalGlobal Impression –Change; CGI-S: Clinical Global Impression – Severity;CI: confidence interval; CMAI: Cohen-Mansfield Agitation Inventory; MMSE:Minimum Mental State Examination; NPI: Neuropsychiatric Inventory; OR: oddsratio; RCT: randomized controlled trial; WMD: weighted mean difference.

Competing interestsThe authors declare that they have no competing interests.

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LEData type,

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LEData type,

continuous; effect measure, weighted mean difference; analysis model,

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LEcontinuous; effect measure, weighted mean difference; analysis model,

Is a forest plot of specific NPI psychosis subscales

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LEIs a forest plot of specific NPI psychosis subscalesData type, continuous;

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LEData type, continuous;effect measure, weighted mean difference; analysis model, fixed effects;

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LEeffect measure, weighted mean difference; analysis model, fixed effects;

Is a forest plot of specific BEHAVE-AD psychosis

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LEIs a forest plot of specific BEHAVE-AD psychosis

subscales on dementia patients in subgroup analyses.

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LEsubscales on dementia patients in subgroup analyses. Data type,

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LEData type,

continuous; effect measure, weighted mean difference; analysis model,

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LEcontinuous; effect measure, weighted mean difference; analysis model,fixed effects; statistical method, inverse variance.

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LEfixed effects; statistical method, inverse variance.

Is a table presenting the quality assessment on

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LEIs a table presenting the quality assessment on

NPI of all included studies in dementia patients.

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LENPI of all included studies in dementia patients.

Is a table presenting the quality assessment on

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LEIs a table presenting the quality assessment on

BPRS of all included studies in dementia patients.

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LEBPRS of all included studies in dementia patients.

Is a table presenting the quality assessment on

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Is a table presenting the quality assessment onBEHAVE-AD of all included studies in dementia patients.

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BEHAVE-AD of all included studies in dementia patients.

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are the newest and most comprehensive attempt to quan-

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are the newest and most comprehensive attempt to quan-titatively synthesize the efficacy and safety of atypical

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titatively synthesize the efficacy and safety of atypicalantipsychotics for neuropsychiatric symptoms of dementia

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antipsychotics for neuropsychiatric symptoms of dementiapatients, suggesting a moderate benefit in neuropsychiatric

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patients, suggesting a moderate benefit in neuropsychiatricoutcomes from antipsychotics. Our meta-analysis results

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outcomes from antipsychotics. Our meta-analysis resultsindicate that for dementia patients who have neuropsychiatric

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indicate that for dementia patients who have neuropsychiatricdisturbances, atypical antipsychotics may be considered as a

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disturbances, atypical antipsychotics may be considered as atherapeutic option. However, it is notable that the decision to

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therapeutic option. However, it is notable that the decision touse these medicines needs to be considered in light of the

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use these medicines needs to be considered in light of theadverse effects, cost and feasibility. As recommended, for

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adverse effects, cost and feasibility. As recommended, fordementia patients with neuropsy

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dementia patients with neuropsychiatric symptoms, excluding

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chiatric symptoms, excludingdementia patients with neuropsychiatric symptoms, excludingdementia patients with neuropsy

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dementia patients with neuropsychiatric symptoms, excludingdementia patients with neuropsymedical and environmental factors, drug therapy should be

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medical and environmental factors, drug therapy should beused to manage neuropsychia

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used to manage neuropsychiatric symptoms. Overall, our

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tric symptoms. Overall, ourused to manage neuropsychiatric symptoms. Overall, ourused to manage neuropsychia

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used to manage neuropsychiatric symptoms. Overall, ourused to manage neuropsychiameta-analysis results indicate

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meta-analysis results indicate a benefit in neuropsychiatric

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a benefit in neuropsychiatricsymptoms for dementia patients from atypical antipsychotics.

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symptoms for dementia patients from atypical antipsychotics.

Conclusion

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ConclusionObvious benefits were observed for symptomatic efficacy

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Obvious benefits were observed for symptomatic efficacyon psychiatric symptoms and cognitive functions of ari-

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on psychiatric symptoms and cognitive functions of ari-piprazole and risperidone after statistically combiningRETRACTED A

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piprazole and risperidone after statistically combiningthe trials. The higher risks for adverse events may offsetRETRACTED A

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the trials. The higher risks for adverse events may offsetthe efficacy of atypical antipsychotics for treatment ofRETRACTED A

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the efficacy of atypical antipsychotics for treatment of

Additional file 8:

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Additional file 8: Is a table presenting the quality assessment on

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Is a table presenting the quality assessment onCGI-C of all included studies in dementia patients.

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CGI-C of all included studies in dementia patients.

Additional file 9:

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Additional file 9: Is a table presenting the quality assessment on

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Is a table presenting the quality assessment onMMSE of all included studies in dementia patients.

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MMSE of all included studies in dementia patients.

Additional file 10:

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Additional file 10:adverse events of all included studies in dementia patients.

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adverse events of all included studies in dementia patients.

Additional file 11:

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Additional file 11:all-cause dropouts in dementia patients.

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all-cause dropouts in dementia patients.effect measure, odds ratio; analysis model, fixed effects; statistical

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effect measure, odds ratio; analysis model, fixed effects; statisticalmethod, Mantel

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method, Mantel

Authors’ contributionsLiT made substantial contributions to the conception and design, acquisitionof data, analysis and interpretation of data, and was involved in drafting aswell as revising it critically for important intellectual content. H-FW and M-STcontributed to designing the study, interpreting the data and revising themanuscript. JW, C-CT, X-FM and CW contributed to trial selection and dataextraction and also helped to revise the manuscript. J-TY and LaT contributedto designing the study and revising the manuscript. All authors gave finalapproval of the version to be published, and agree to be accountable for allaspects of the work in ensuring that questions related to the accuracy orintegrity of any part of the work are appropriately investigated and resolved.

AcknowledgementsThis work was supported by grants from the National Natural ScienceFoundation of China (81000544, 81171209, 81371406) and ShandongProvincial Natural Science Foundation, China (ZR2010HQ004, ZR2011HZ001).

Author details1College of Medicine and Pharmaceutics, Ocean University of China, Qingdao266000, China. 2Department of Neurology, Qingdao Municipal Hospital,School of Medicine, Qingdao University, Qingdao 266071, China.3Department of Neurology, Qingdao Municipal Hospital, Nanjing MedicalUniversity, Nanjing 210000, China.

Received: 13 August 2014 Accepted: 28 January 2015

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