Yunusa I, Alsumali A, Garba AE, et al. Assessment of Reported Comparative Effectiveness and Safety of Atypical Antipsychotics in the Treatment of Behavioral and Psychological Symptoms of Dementia: A Network Meta-analysis. JAMA Netw Open. 2019 Mar 1;2(3):e190828. doi: 10.1001/jamanetworkopen.2019.0828. (Systematic review)

Importance: Atypical antipsychotics offer modest effectiveness compared with placebo but with serious safety risks, including a boxed warning for the risk of death in the treatment of behavioral and psychological symptoms of dementia (BPSD). Their comparative effectiveness and safety are not fully known.

Objective: To assess the relative benefits and safety of atypical antipsychotics in the treatment of BPSD shown in randomized clinical trials using network meta-analysis.

Data Sources: PubMed/MEDLINE, Embase, PsychINFO, and Cochrane Library were searched from their inception until May 31, 2018. Key terms included dementia and atypical antipsychotics.

Study Selection: Randomized clinical trials comparing any atypical antipsychotic with another atypical antipsychotic or with placebo were included in the analysis.

Data Extraction and Synthesis: Two independent reviewers used a standardized data extraction and quality assessment form. Random-effects network meta-analyses were performed. Effect sizes were reported as standardized mean differences (SMDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes with 95% CIs. In addition to ORs, the surface under the cumulative ranking curve (SUCRA) was ascertained, which represents the percentage of the effectiveness or safety for each treatment compared with a hypothetical treatment that would be ranked first without uncertainty.

Main Outcomes and Measures: The primary effectiveness outcome assessed was the Neuropsychiatric Inventory (NPI); secondary effectiveness outcomes were the Brief Psychiatric Rating Scale (BPRS) and Cohen-Mansfield Agitation Inventory (CMAI). The primary safety outcomes were death and cerebrovascular adverse events (CVAEs). Secondary safety outcomes were extrapyramidal signs/symptoms; somnolence/sedation; falls, fracture, or injury; and urinary tract infection/incontinence.

Results: Seventeen studies (5373 patients) were included. The mean (SD) age of all participants was 80.8 (3.1) years, and most were women (3748 [69.8%]). Compared with placebo, aripiprazole was associated with improvement in outcomes on the NPI (SMD, -0.17; 95% CI, -0.31 to -0.02), BPRS (SMD, -0.20; 95% CI, -0.35 to -0.05), and CMAI (SMD, -0.30; 95% CI, -0.55 to -0.05); quetiapine was associated with improvement in outcomes on the BPRS (SMD, -0.24; 95% CI, -0.46 to -0.01), and risperidone was associated with improvement in outcomes on the CMAI (SMD, -0.26; 95% CI, -0.37 to -0.15). Differences between atypical antipsychotics were not significant for effectiveness, death, or CVAE. Compared with placebo, risperidone (OR, 3.85; 95% CI, 1.55-9.55) and olanzapine (OR, 4.28; 95% CI, 1.26-14.56) were associated with increased risk of CVAEs. The SUCRA estimated relative ranking of treatments suggested that aripiprazole might be the most effective and safe atypical antipsychotic and that olanzapine provides the least benefit overall; however, these results should be interpreted with caution where point estimates (OR and SMD) show that there is no statistically significant difference.

Conclusions and Relevance: This network meta-analysis supports the existence of a trade-off between the effectiveness and safety of atypical antipsychotics in the treatment of BPSD and confirms that a single most effective and safe treatment option does not exist. Clinicians should individualize the assessment of safety risks against expected benefits when prescribing these medications to patients with dementia.

Discipline Area Score
Psychiatry 7 / 7
Geriatrics 7 / 7
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Internal Medicine 6 / 7
Neurology 5 / 7
Comments from MORE raters

General Internal Medicine-Primary Care(US) rater

This new information, for most primary care providers, can inform conversations with families about whether or not to use an atypical antipsychotic and the effectiveness and harms of individual agents.

Geriatrics rater

Managing behavioral disorders in dementia is a common challenge in geriatrics, primary care, and even in acute settings such as the emergency department and inpatient wards. This comprehensive network meta-analysis leaves readers with more questions than answers, such as how to balance the potential harms versus benefits among the myriad pharmacologic options for the individual patient.

Geriatrics rater

A very useful summary of the efficacy and risk profiles of the 4 atypical antipsychotics when used in patients with behavioral symptoms of dementia, and a network comparison of the four. I suspect this will change how people prescribe these drugs. I predict less use of olanzapine and risperidol and increased use of aripiprazole (which I have not seen used as much).

Internal Medicine rater

In this article, the authors attempt to distinguish between antipsychotics when used for behavioral disturbances in dementia. They perform a network meta-analysis to make up for the fact that these medications were never and will never be compared in a head-to-head fashion. In the end, they settle on statistical differences that are probably clinically very unimportant (fractions of a point on behavioral scales) to show potential differences. These are not likely to matter to clinicians. These medicines will not be compared head-to-head. They are all unsafe. I do not believe this paper helps us pick among them and would not recommend it to my fellow hospitalists.

Neurology rater

This is an important area of research but, unfortunately, no meta-analytic methods can resolve what only comparative clinical trials can, which are unlikely to get funded. The outcome of this analysis leaves us with the same uncertainty as when we started (although at least we can be reassured that uncertainty is the only certainty!).

Neurology rater

The comparison between antipsychotics should take in account the respective dosage used in studies.

Psychiatry rater

Even medications within the same class are not created equal. This analysis of 17 studies confirms there is a necessary trade-off between the effectiveness and safety of each antipsychotic drug used for the treatment of neuropsychiatric symptoms associated with dementia. For this patient population, risk for death may not be the most important safety concern for families. What is most important to families should form the basis for any medication intervention.
Comments from EvidenceAlerts subscribers

Dr. Ahmed Elaghoury (5/7/2019 10:18 AM)

I don't think aripiprazole is a trade-off, as might be suggested here. Network metanalyses are invalid to give head-to-head conclusions. They give indirect impressions, derived from various studies. The trade-off might be a balancing between nonpharmacologic and pharmacologic interventions while keeping medications for brief and interrupted doses when the healthcare process or safety of patients are hugely disrupted. All antipsychotics have been repeatedly shown to be hazardous with this group of patients.

Dr. Caroline Knight (4/12/2019 2:26 PM)

Aripiprazole is a relatively new drug. It would have been interesting to know how many of the studies and patients were given which drug. I would hazard a guess that there are more data for risperidone and olanzepine that have been around longer than for aripiprazole ... and the picture may change when there are more data available for the newer drug.