[Summary text]
For more information see: Orgeta, Vasiliki, et al. "Efficacy of Antidepressants for Depression in Alzheimer’s Disease: Systematic Review and Meta-Analysis." Journal of Alzheimer's Disease 58.3 (2017): 725-733.
For more information see:
Jones, Helen E., et al. "The effect of treatment with selective serotonin reuptake inhibitors in comparison to placebo in the progression of dementia: a systematic review and meta-analysis."
Age and ageing 45.4 (2016): 448-456.
Study design: Randomized controlled trial
Study grouping: Parallel group
Baseline Characteristics
Intervention 1
Control
Included criteria: To summarize, 186 study participants were diagnosedwith probable Alzheimer’s disease as defined by the NationalInstitute of Neurological and Communicative Disorders andStroke–Alzheimer’s Disease and Related Disorders Associ-ation criteria (26) and had Mini-Mental State Examination(27) scores ranging from 5 to 28. Additional inclusion cri-teria included“clinically significant agitation”for which aphysician determined that medication was appropriateand which was rated as occurring“very frequently”or“frequently”with“moderate”or“marked”severity, asassessed by the agitation/aggression item of the NPI.
Excluded criteria: Exclusion criteria included a current major depressive episodeor psychosis requiring antipsychotic treatment. A readilyavailable caregiver was required, to provide information foroutcome measures and to supervise medication use.
Pretreatment: The baseline characteristics were similar between thecitalopram and placebo groups, except that the placebogroup had a lower mean score on the Mini-Mental State Ex-amination
Intervention Characteristics
Intervention 1
Control
BPSD (NPI, non-mood subscale)
Sponsorship source: Supported by National Institute on Aging (NIA) and NIMH grantR01AG031348, and in part by NIH grant P50-AG05142 (to University ofSouthern California and Dr. Schneider).
Country: USA
Setting: Multicenter
Comments: ClinicalTrials.gov identifier: NCT00898807
Authors name: Leonpacher
Institution: Department of Psychiatry
Email: anton_porsteinsson@urmc.rochester.edu
For more information see: Orgeta, Vasiliki, et al. "Efficacy of Antidepressants for Depression in Alzheimer’s Disease: Systematic Review and Meta-Analysis." Journal of Alzheimer's Disease 58.3 (2017): 725-733.
For more information see: Orgeta, Vasiliki, et al. "Efficacy of Antidepressants for Depression in Alzheimer’s Disease: Systematic Review and Meta-Analysis." Journal of Alzheimer's Disease 58.3 (2017): 725-733.
For more information see: Orgeta, Vasiliki, et al. "Efficacy of Antidepressants for Depression in Alzheimer’s Disease: Systematic Review and Meta-Analysis." Journal of Alzheimer's Disease 58.3 (2017): 725-733.
For more information see:
Jones, Helen E., et al. "The effect of treatment with selective serotonin reuptake inhibitors in comparison to placebo in the progression of dementia: a systematic review and meta-analysis."
Age and ageing 45.4 (2016): 448-456.
For more information see:
Jones, Helen E., et al. "The effect of treatment with selective serotonin reuptake inhibitors in comparison to placebo in the progression of dementia: a systematic review and meta-analysis."
Age and ageing 45.4 (2016): 448-456.
For more information see: Orgeta, Vasiliki, et al. "Efficacy of Antidepressants for Depression in Alzheimer’s Disease: Systematic Review and Meta-Analysis." Journal of Alzheimer's Disease 58.3 (2017): 725-733.
For more information see:
Jones, Helen E., et al. "The effect of treatment with selective serotonin reuptake inhibitors in comparison to placebo in the progression of dementia: a systematic review and meta-analysis."
Age and ageing 45.4 (2016): 448-456.
Wrong intervention
Wrong outcomes
Wrong patient population
Wrong intervention
Abstract only
Wrong patient population
Wrong patient population
Wrong patient population
Wrong study design
Wrong comparator
Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence
Quote: "Random allocation was stratified by centre and done with a computer-generated randomisation sequence with randomly varying block sizes (block sizes of 3 or 6)".
Judgement comment: Insufficient information on sequence generation
Judgement Comment: From Drye 2012: Participants are randomized in a 1:1 ratio to receive citalopram or matching placebo. Thetreatment assignment schedule was created by the coordinating center using a documented,auditable SAS program (SAS/STAT® software, Version 9.1 of the SAS System forWindows; Copyright © 2000–2004 SAS Institute Inc, Cary NC, USA) and was generated inblocks of permuted length and stratified by clinical center. Clinical centers request treatmentassignments using an online program accessible via the CitAD data system.
Judgement comment: random allocation using computer program to generate the sequence
Judgement comment: Insufficient information on sequence generation
Judgement comment: Insufficient information on sequence generation
Quote: "Patients were randomly assigned to receive either citalopram, perphenazine, or placebo according to a 3:3:2 ratio. "
Judgement comment: "Insufficient information on sequence generation"
Judgement comment: From Drye et al. Citalopram for agitation in Alzheimer’s disease: Design and methods. Alzheimer’s & Dementia 8 (2012) 121–130: Quote "Participants are randomized in a 1:1 ratio to receive citalopram or matching placebo. The treatment assignment schedule was created by the coordinating center using a documented, auditable SAS program (SAS/STAT software, version 9.1; SAS Institute, Cary, NC) and was generated in blocks of permuted length and stratified by clinical center. Clinical centers request treatment assignments using an online program accessible through the CitAD data system."
Quote: "Participants were randomized by the study’s Coordinating Center (PI: BKM), in a 1:1 ratio, to receive sertraline or placebo as previously described (24)."
From reference: Martin et al. Design of Depression in Alzheimer's Disease Study-2. Am J Geriatr Psychiatry. 2006 Nov;14(11):920-30.
Quote: "Patients are randomized in a 1:1 ratio to receive
sertraline or placebo. The randomization schedule is
stratified by clinical site and uses blocks of permuted
length. The auditable, documented treatment assignment
lists were generated by the trial’s coordinating
center using the RALLOC procedure of Stata Statistical
Software Release 8.2.27"
From reference: Martin et al. Design of Depression in Alzheimer's Disease Study-2. Am J Geriatr Psychiatry. 2006 Nov;14(11):920-30.
Quote: "Patients are randomized in a 1:1 ratio to receive
sertraline or placebo. The randomization schedule is
stratified by clinical site and uses blocks of permuted
length. The auditable, documented treatment assignment
lists were generated by the trial’s coordinating
center using the RALLOC procedure of Stata Statistical
Software Release 8.2.27"
Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment
Judgement comment: Insufficient information on allocation concealment
Judgement comment: Insufficient information on allocation concealment
Judgement Comment: From Drye 2012: The corresponding medication kits are packaged by the Johns Hopkins Bayview Medical Center Pharmacy to contain either citalopram or placebo according to the treatment assignment schedule and are labeled by medication kit ID only. Masking is accomplished by over-encapsulatingcitalopram tablets and creating matching placebos both backfilled with microcrystallinecellulose into opaque capsules.
Judgement comment: masked treatment assignment was communicated by telephone to all staff.
Judgement comment: Insufficient information on allocation concealment
Jugdement comment: Insufficent informatio on allocation concealment
Judgement comment: "Insufficient information on allocation concealment"
Judgement comment: From Drye et al. Citalopram for agitation in Alzheimer’s disease: Design and methods. Alzheimer’s & Dementia 8 (2012) 121–130: Quote "Participants are randomized in a 1:1 ratio to receive citalopram or matching placebo. The treatment assignment schedule was created by the coordinating center using a documented, auditable SAS program (SAS/STAT software, version 9.1; SAS Institute, Cary, NC) and was generated in blocks of permuted length and stratified by clinical center. Clinical centers request treatment assignments using an online program accessible through the CitAD data system."
From reference: Martin et al. Design of Depression in Alzheimer's Disease Study-2. Am J Geriatr Psychiatry. 2006 Nov;14(11):920-30.
Quote: " Randomized treatment
assignment is accomplished through the use of
sealed, opaque envelopes containing unique medication
kit identifiers, which are opened sequentially at each site at the time of randomization."
From reference: Martin et al. Design of Depression in Alzheimer's Disease Study-2. Am J Geriatr Psychiatry. 2006 Nov;14(11):920-30.
Quote: " Randomized treatment
assignment is accomplished through the use of
sealed, opaque envelopes containing unique medication
kit identifiers, which are opened sequentially at each site at the time of randomization."
Performance bias due to knowledge of the allocated interventions by participants and personnel during the study
Quote: "The trial was double-blind, with drugs and placebo identical in appearance for every antidepressant. Referring clinicians and research workers who did baseline and follow-up assessments were masked to group allocation, as were patients and pharmacies. Statisticians were masked to group identity until analyses were complete".
Judgement comment: Unclear who is double-blinded in the study
Judgement Comment: Treatments are administeredin a double-masked fashion; participants, their caregivers and clinical center personnel areall masked to treatment assignment.
Judgment comment: patient, caregivers and investigators were all masked to the assignment
Judgement comment: both participants and personnel were blinded to treatment (double-blinded)
Judgement comment: Insufficient information on blinding
Quote: "The study was a randomized, double-blind, placebo-controlled trial lasting for the duration of inpatient hospitalization, up to 17 days."
Quote: "All clinical center personnel and participants weremasked to treatment assignment."
Judgment comment: Unclear who the blinding applies to.
Judgment comment: Unclear who the blinding applies to.
Detection bias due to knowledge of the allocated interventions by outcome assessors
Quote: "The trial was double-blind, with drugs and placebo identical in appearance for every antidepressant. Referring clinicians and research workers who did baseline and follow-up assessments were masked to group allocation, as were patients and pharmacies. Statisticians were masked to group identity until analyses were complete".
Judgement comment: Unclear who is double-blinded in the study
Judgement Comment: Nothing mentioned on outcome assessors
Judgment comment:caregivers and investigators were all masked to the assignment
Judgement comment: outcome assesors were blinded to treatment
Judgement comment: Insufficient information on blinding
Judgment comment: Insufficient information on blinding of outcome assesors
Quote: "All clinical center personnel and participants weremasked to treatment assignment."
Judgment comment: Unclear who the blinding applies to.
Judgment comment: Unclear who the blinding applies to.
Attrition bias due to amount, nature or handling of incomplete outcome data
Quote: "We did modelling with the assumption that data were missing at random, and included predictors of missing data (treatment group and centre) in the modelling".
Quote: "Analyses were pragmatic and based on the intention-to-treat sample".
Quote: "The primary efficacy analyses were at endpoint, defined as the last (postrandomization) observation carried forward (LOCF) to week 8 and week 20, and were conducted on the intent-to-treat (ITT) population".
Judgement Comment: Porsteinsson et al (ref 20) provide a flowchart including dropouts. Reasons for missing data are provided and balanced between groups
Judgment comment: all analysis were performed with ITT with last observation caried forward
Judgement comment: intention-to treat. Non-completers score at week 4 were carried forward.
Judgement comment: 4 out of 24 in the placebo group, and 2 out of 17 in the fluoxetine group withdrew from the study all within the first two weeks of the trial. Not considered to introduce bias.
Judgement comment: Used ITT with last observation caried forward.
Judgement comment: Unclear reporting on incomplete outcome data.
Quote: "Primary assessment of efficacy was based on intention-totreat (ITT) comparison of the difference in the NBRS-A scores at week 9 and comparison at week 9 for the mADCS-CGIC. Crude between-treatment difference at week 9 NBRS-A scores was assessed using a t test."
Quote: "Efficacy was assessed using logistic regressions and mixed effects models in an intention to treat (ITT) analysis with imputation of missing data"
Quote: "All analyses were intention-to-treat and performed according to patients’ original treatment assignments (i.e. randomization to sertraline or placebo). Missing outcomes were imputed using the method of multiple imputation(26). Prediction models of the missing data were estimated based on the patients’ other available baseline and follow-up data, and these models were used to impute the missing outcomes five times. The results of five imputations were synthesized using simple combination rules(27) to yield estimates of treatment comparisons."
Reporting bias due to selective outcome reporting
Quote: "This study is registered, number ISRCTN88882979".
Quote: "The primary outcome was clinical eff ectiveness of sertraline and mirtazapine in terms of reduction of depression as measured by CSDD score.19 Cost-eff ectiveness (client service receipt inventory20) of the two interventions will be reported as the primary outcome elsewhere".
Judgement comment: The study protocol is available, and all clinical outcomes have been reported.
Judgement comment: The study protocol is not available, but apeears to include all expected outcomes.
Judgement Comment: Matches study protocol.
Judgement comment: The study protocol is not available, but apeears to include all expected outcomes.
Judgement comment: The study protocol is not available, but apeears to include all expected outcomes.
Judgement comment: The study protocol is not available, but results from CGI and FIM have not been reported, even though they are described in the method section.
Judgement comment: The study protocol is not available, but apeears to include all expected outcomes.
Quote: "clinicaltrials.gov Identifier: NCT00898807"
Judgement comment: The study protocol is available, and all pre-specified outcomes have been reported.
Quote: Trial Registration: www.clinicaltrials.gov NCT00086138.
Judgement comment: The study protocol is available, and all pre-specified outcomes are reported.
Quote: "Trial Registration: NCT00086138"
Judgement comment: The study protocol report that the intervention period is of 24 weeks. Outcomes were pre-specified at 12 weeks (Rosenberg et al.), but not at 24 weeks
Bias due to problems not covered elsewhere in the table
Quote: "The protocol was changed during recruitment. Owing to a call for extra funding after slower than expected recruitment, the sample size needed for the trial was statistically reviewed by the data monitoring and ethics committee when there were 75 participants with data for 13-week follow-up. The parameters of the sample size calculation were not changed (SD 5; SES 0·4), but the new target was calculated on the basis of reported values that had greater precision than did the prestudy assumptions. An extended recruitment period was agreed with a revised target of 339 participants for the sample (113 in every group). This change involved unmasking of a statistician (Clare Rutterford, Clinical Trials Unit, King’s College London, UK), who was not involved in the fi nal analyses, to the identity of patients in the placebo group."
Judgement comment: The change in the protocol made were handled in a way that appears to be free from bias.
Quote: "Contract/grant sponsor: Pfizer Inc."
Judgement comment: The role of funding in the study is unclear
Judgement Comment: No other apparent sources of bias
The study appears to be free from other sources of bias.
Quote: "Contract/grant sponsor: Pfizer Inc."
Judgement comment: The role of funding in the study is unclear
Judgement comment:The study appears to be free from other sources of bias.
Judgement comment: The study appears to be free from other sources of bias.
Judgement comment: The study appears to be free from other sources of bias.
Quote: "Role of the funding source NIMH scientific collaborators participated on the trial’s Steering Committee. Sertraline and matching placebo were provided by Pfizer, Inc., which did not otherwise participate in the design or conduct of the trial."
Judgement comment: The study apears to be from other sources of bias.
Quote: "NIMH scientific collaborators participated on the trial’s Steering Committee. Sertraline and matching placebo were provided by Pfizer, Inc., which did not otherwise participate in the design or conduct of the trial. After database lock and study unblinding, the corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. All co-investigators had access to the raw data. ."
Judgement comment: The study apears to be from other sources of bias.