Pharmacological treatments for alleviating agitation in dementia: a systematic review and network meta-analysis : Medications for agitation in dementia: network meta-analysis
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Abstract
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<h5 class="section-title" id="d8689239e380">Aims</h5>
<p id="d8689239e382">To determine the most efficacious and acceptable treatments of
agitation in dementia.</p>
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<h5 class="section-title" id="d8689239e385">Methods</h5>
<p id="d8689239e387">MEDLINE, EMBASE, PsycINFO, CENTRAL and
<a data-untrusted="" href="http://clinicaltrials.gov" id="d8689239e389" target="xrefwindow">http://clinicaltrials.gov</a>
were searched up to 7 February 2017. Two independent reviewers selected randomized
controlled trials (RCTs) of treatments to alleviate agitation in people with all‐types
dementia. Data were extracted using standardized forms and study quality was assessed
using the revised Cochrane Risk of Bias Tool for RCTs. Data were pooled using meta‐analysis.
The primary outcome, efficacy, was 8‐week response rates defined as a 50% reduction
in baseline agitation score. The secondary outcome was treatment acceptability defined
as treatment continuation for 8 weeks.
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<h5 class="section-title" id="d8689239e393">Results</h5>
<p id="d8689239e395">Thirty‐six RCTs comprising 5585 participants (30.9% male; mean
± standard deviation
age, 81.8 ± 4.9 years) were included. Dextromethorphan/quinidine [odds ratio (OR)
3.04; 95% confidence interval (CI), 1.63–5.66], risperidone (OR 1.96; 95% CI, 1.49–2.59)
and selective serotonin reuptake inhibitors as a class (OR 1.61; 95% CI, 1.02–2.53)
were found to be significantly more efficacious than placebo. Haloperidol appeared
less efficacious than nearly all comparators. Most treatments had noninferior treatment
continuation compared to placebo, except oxcarbazepine, which was inferior. Findings
were supported by subgroup and sensitivity analyses.
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<h5 class="section-title" id="d8689239e398">Conclusions</h5>
<p id="d8689239e400">Risperidone, serotonin reuptake inhibitors as a class and dextromethorphan/quinidine
demonstrated evidence of efficacy for agitation in dementia, although findings for
dextromethorphan/quinidine were based on a single RCT. Our findings do not support
prescribing haloperidol due to lack of efficacy, or oxcarbazepine due to lack of acceptability.
The decision to prescribe should be based on comprehensive consideration of the benefits
and risks, including those not evaluated in this meta‐analysis.
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Healthcare providers, consumers, researchers and policy makers are inundated with unmanageable amounts of information, including evidence from healthcare research. It has become impossible for all to have the time and resources to find, appraise and interpret this evidence and incorporate it into healthcare decisions. Cochrane Reviews respond to this challenge by identifying, appraising and synthesizing research-based evidence and presenting it in a standardized format, published in The Cochrane Library (www.thecochranelibrary.com).<p><i>The Cochrane Handbook for Systematic Reviews of Interventions</i> contains methodological guidance for the preparation and maintenance of Cochrane intervention reviews. Written in a clear and accessible format, it is the essential manual for all those preparing, maintaining and reading Cochrane reviews. Many of the principles and methods described here are appropriate for systematic reviews applied to other types of research and to systematic reviews of interventions undertaken by others. It is hoped therefore that this book will be invaluable to all those who want to understand the role of systematic reviews, critically appraise published reviews or perform reviews themselves.
Objectives To investigate the association between antidepressant treatment and risk of several potential adverse outcomes in older people with depression and to examine risks by class of antidepressant, duration of use, and dose. Design Cohort study of people aged 65 and over diagnosed as having depression. Setting 570 general practices in the United Kingdom supplying data to the QResearch primary care database. Participants 60 746 patients diagnosed as having a new episode of depression between the ages of 65 and 100 years from 1 January 1996 to 31 December 2007 and followed up until 31 December 2008. Main outcome measures Hazard ratios associated with antidepressant use for all cause mortality, attempted suicide/self harm, myocardial infarction, stroke/transient ischaemic attack, falls, fractures, upper gastrointestinal bleeding, epilepsy/seizures, road traffic accidents, adverse drug reactions, and hyponatraemia, adjusted for a range of potential confounding variables. Hazard ratios were calculated for antidepressant class (tricyclic and related antidepressants, selective serotonin reuptake inhibitors, other antidepressants), dose, and duration of use and for commonly prescribed individual drugs. Results 54 038 (89.0%) patients received at least one prescription for an antidepressant during follow-up. A total of 1 398 359 antidepressant prescriptions were issued: 764 659 (54.7%) for selective serotonin reuptake inhibitors, 442 192 (31.6%) for tricyclic antidepressants, 2203 (0.2%) for monoamine oxidase inhibitors, and 189 305 (13.5%) for the group of other antidepressants. The associations with the adverse outcomes differed significantly between the antidepressant classes for seven outcomes. Selective serotonin reuptake inhibitors were associated with the highest adjusted hazard ratios for falls (1.66, 95% confidence interval 1.58 to 1.73) and hyponatraemia (1.52, 1.33 to 1.75) compared with when antidepressants were not being used. The group of other antidepressants was associated with the highest adjusted hazard ratios for all cause mortality (1.66, 1.56 to 1.77), attempted suicide/self harm (5.16, 3.90 to 6.83), stroke/transient ischaemic attack (1.37, 1.22 to 1.55), fracture (1.64, 1.46 to 1.84), and epilepsy/seizures (2.24, 1.60 to 3.15), compared with when antidepressants were not being used. Tricyclic antidepressants did not have the highest hazard ratio for any of the outcomes. Significantly different associations also existed between the individual drugs for the same seven outcomes; trazodone (tricyclic antidepressant), mirtazapine, and venlafaxine (both in the group of other antidepressants) were associated with the highest rates for some of these outcomes. Absolute risks over 1 year for all cause mortality were 7.04% for patients while not taking antidepressants, 8.12% for those taking tricyclic antidepressants, 10.61% for selective serotonin reuptake inhibitors, and 11.43% for other antidepressants. Conclusions Selective serotonin reuptake inhibitors and drugs in the group of other antidepressants were associated with an increased risk of several adverse outcomes compared with tricyclic antidepressants. Among individual drugs, trazodone, mirtazapine, and venlafaxine were associated with the highest risks for some outcomes. As this is an observational study, it is susceptible to confounding by indication, channelling bias, and residual confounding, so differences in characteristics between patients prescribed different antidepressant drugs that could account for some of the associations between the drugs and the adverse outcomes may remain. Further research is needed to confirm these findings, but the risks and benefits of different antidepressants should be carefully evaluated when these drugs are prescribed to older people.
[1
]School of Pharmacy; Monash University Malaysia; Selangor Malaysia
[2
]Clinical Trials and Evidence Base Syntheses Research Unit (CTEBs RU), Department of
Clinical Pharmacy, Faculty of Pharmacy; Mahasarakham University; Mahasarakham Thailand
[3
]Department of Psychiatry, King Chulalongkorn Memorial Hospital, Faculty of Medicine;
Chulalongkorn University; Bangkok Thailand
[4
]Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences;
Monash University; Australia
[5
]Kolling Institute of Medical Research; Royal North Shore Hospital and University of
Sydney; St Leonards NSW Australia
[6
]Center of Pharmaceutical Outcomes Research (CPOR), Department of Pharmacy Practice,
Faculty of Pharmaceutical Sciences; Naresuan University; Phitsanulok Thailand
[7
]Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes
(PICO), Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform;
Monash University Malaysia; Bandar Sunway Selangor Malaysia
[8
]School of Pharmacy; University of Wisconsin; Madison USA
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