Dementia Care Faces Lack of Safe and Effective Atypical Antipsychotic Treatment


Findings from a recent meta-analysis of the number of atypical antipsychotics available for treatment of behavioral and psychological symptoms of dementia suggest that a clear trade-off exists between effectiveness and safety, with no clear winner emerging.

Ismaeel Yunusa, PharmD

Ismaeel Yunusa, PharmD, a graduate research assistant and PhD candidate at the Massachusetts College of Pharmacy and Health Sciences

Ismaeel Yunusa, PharmD

A clear trade-off exists between the effectiveness and safety of available atypical antipsychotics for the treatment of behavioral and psychological symptoms of dementia (BPSD), according to a recent study.1 The findings further support the complicated treatment landscape that exists for the symptomatic management of dementia.

After assessing 17 studies including more than 5000 patients with dementia, the investigators, led by Ismaeel Yunusa, PharmD, a graduate research assistant and PhD candidate at the Massachusetts College of Pharmacy and Health Sciences, determined that clinicians should take a personalized approach to assess safety risk against the expected benefits when prescribing atypical antipsychotics to patients with dementia.

“Insufficient evidence exists on which atypical antipsychotic is both safest and most beneficial across several measures for people with dementia, and this study suggests that a single most effective and safe treatment option may not exist,” Yunusa and colleagues wrote.

The findings revealed that in comparison with placebo, aripiprazole was associated with improvement in outcomes on the Neuropsychiatric Inventory (NPI), with standardized mean differences (SMD) of −0.17 (95% CI, −0.31 to −0.02), on the Brief Psychiatric Rating Scale (BPRS; SMD, −0.20; 95% CI, −0.35 to −0.05), and on the Cohen-Mansfield Agitation Inventory (CMAI; SMD, −0.30; 95% CI, −0.55 to −0.05).

Meanwhile, 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).

With regard to BPRS, based on the surface under the cumulative ranking curve (SUCRA), quetiapine (80.2%) and aripiprazole (72.9%) had the highest probability of effectiveness, while with the CMAI, aripiprazole (73.8%) and risperidone (68.6%) had the highest probability of effectiveness.

In an accompanying editorial, Brent P. Forester, MD, MSc and Ipsit Vahia, MD wrote that “clinical decisions are individualized and often dependent on complex subjective factors beyond the application of available clinical trial data,” and as such, research that focuses on the various causes of BPSD can better inform the development of more-targeted behavioral and pharmacologic agents.2

“Furthermore, there is a clear need for leveraging novel technologies that can phenotype behavioral symptoms of dementia and provide a more precise clinical picture to guide decision making,” they continued. “Ultimately, our ability to reduce the burden from these symptoms will depend directly on generating both basic and clinical research and to rapidly translate this into effective interventions.”

When compared with placebo, there were no significant differences between antipsychotics for effectiveness, death, or cerebrovascular adverse events (AEs); however, risperidone (odds ratio [OR], 3.85; 95% CI, 1.55 to 9.55) and olanzapine (OR, 4.28; 95% CI, 1.26 to 14.56) were associated with increased risk for cerebrovascular AEs. With regard to mortality, placebo had the highest probability of safety on the mortality outcome (87.3%), followed by risperidone (55.4%), aripiprazole (37.9%), quetiapine (37.1%), and olanzapine (32.4%) when measured by the SUCRA.

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. Although, as there were no statistical differences in ORs or SMDs, Yunusa and colleagues recommended interpreting the data with caution.

All told, based on SUCRA rankings, placebo had the highest probability of safety on the cerebrovascular AEs outcome (80.4%), followed by aripiprazole (69.1%), quetiapine (65.1%), risperidone (19.6%), and olanzapine (15.8%).

“Although the 3-fold increase in CVAE risk from the use of risperidone corroborates evidence from previous pairwise meta-analyses, the increase associated with olanzapine represents the first significant association from a meta-analysis,” the authors wrote. “Whenever physicians consider prescribing risperidone and olanzapine, risk factors for [cerebrovascular] AEs should be assessed.”

The American Psychiatric Association guidelines and STOPP/START criteria recommend that olanzapine and risperidone should be avoided or used with caution in those who have hypovolemia, a history of cerebrovascular and cardiac diseases, and vascular dementia with a pre-existing high risk for stroke or transient ischemic attack.3-4 The authors noted that this is in line with their findings.


1. Yunusa I, Alsumali A, Garba AE, Regestein QR, Eguale T. JAMA Network Open. 2019;2(3):e190828. doi:10.1001/jamanetworkopen.2019.0828.

2. Forester BP, Vahia I. Behavioral and psychological symptoms—an emerging crisis of the Alzheimer dementia epidemic. JAMA Network Open. 2019;2(3):e190790. doi:10.1001/jamanetworkopen.2019.0790.

3. Reus VI, Fochtmann LJ, Eyler AE, et al. The American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. APA website. doi: 10.1176/appi.books.9780890426807.

4. O’Mahony D, O’Sullivan D, Byrne S, O’Connor MN, Ryan C, Gallagher P. STOPP/START criteria for potentially inappropriate prescribing in older people: version 2. Age Ageing. 2015; 44(2): 213—218. doi: 10.1093/ageing/afu145.

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