Pharmacological treatments for alleviating agitation in dementia: a systematic review and network meta-analysis

Abstract

Aims: To determine the most efficacious and acceptable treatments of agitation in dementia.

Methods: MEDLINE, EMBASE, PsycINFO, CENTRAL and clinicaltrials.gov 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.

Results: 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.

Conclusions: 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.

Keywords: Alzheimer's disease; agitation; dementia; network meta-analysis; pharmacological treatments.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) diagram: the diagram demonstrates the process of review, inclusion and exclusion of studies. RCT, randomized controlled trial; NPI‐A, Neuropsychiatric Inventory–Agitation subscale score

Figure 2

Network map of treatment comparisons for both primary and secondary outcomes: Nodes represented each treatment, while links between the nodes indicated the available direct comparisons between pairs of treatments. The size of the nodes corresponds to the number of studies investigating the treatments. The thickness of the lines corresponds to the number of studies assessing the comparisons. ARI, aripiprazole; CIT, citalopram; DEX/QUI, dextromethorphan/quinidine; DON, donepezil; FLO, fluoxetine; FLV, fluvoxamine; GAL, galantamine; HAL, haloperidol; MEL, melatonin; MEM, memantine; OLA, olanzapine; OXC, oxcarbazepine; PLA, placebo; PRO, propranolol; QUE, quetiapine; RIS, risperidone; RIV, rivastigmine; SER, sertraline; TOP, topiramate; TRA, trazodone; VAL, valproate; YOK, yokukansan

Figure 3

Plots of network meta‐analysis results for primary outcome (8‐week response rates) and secondary outcome (treatment acceptability, dropout rates) when each of medications compared to placebo. OR, odds ratio; CI, confidence interval