Tools for Practice

#206 Agitation in Dementia: Quantifying the effects of antipsychotics

What are the benefits and harms of antipsychotics for agitation in dementia?

A strong placebo effect explains most of the perceived efficacy, with antipsychotics providing little additional improvement over placebo on agitation scales (~additional points out of 144)However, 50% improvement in behaviour occurs in ~46% on antipsychotic versus ~33% on placebo. Harms are serious (increased death ocerebrovascular events for 1 in ~80, for each over placebo) and common (somnolence or gait troubles 1 in ~10 or 20, for each). Antipsychotics should be reserved for cases of severe aggression and withdrawal attempted as soon as possible.  

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Six systematic reviews [5-16 Randomized Controlled Trials (RCTs), 856-5,110 patients], most followed ~10-12 weeks.1-6 Statistically significant unless indicated: 
  • Placebo has large effects.7 Example: 
    • Improves 11-points on 144-point neuropsychiatric scale, a clinically meaningful difference. 
  • Atypical antipsychotics:  
    • Mean improvement over placebo on multiple scales trivial at best:1-3  
      • Example 3-points on 144-point neuropsychiatric scaleunlikely clinically meaningful. 
    • Individual antipsychotics (risperidone,2 olanzapine,2 quetiapine5) found similar. 
      • Exception was improvement on the global change scale of 0.32 points on  7-point scale, likely clinically detectable. 
    • Proportion of patients attaining 50% improvement in scales.4  
      • Example: Risperidone 46% versus 33%, Number Needed to Treat (NNT)=8. 
  • Atypical antipsychotic harms:  
    • Stopping due to adverse events:2 Number Needed to Harm (NNH)=13-39. 
    • Serious harms: Death (NNH=77-84),1,4 cerebrovascular events (NNH=48-104).1,2,4 
    • Mini-Mental Status Exam 0.73 worse (not significant).4 
    • Other:1,2,4 Somnolence (NNH=7-11), gait abnormalities (NNH=11-20), extrapyramidal symptoms (NNH=16-44), and peripheral edema (NNH=20-25). 
  • First generation antipsychotics (example haloperidol) appear to have similar rates of harms but inconsistent benefits.6   
  • Cholinesterase inhibitors, SSRIs, trazodone, and valproate provide no meaningful improvement in agitation.8-11 
    • Benzodiazepines may approach antipsychotics for efficacy in agitation but also have harms.12 
  • Stopping antipsychotics may reduce death (NNT=4 at two years) with little impact on neuropsychiatric symptoms.13 
  • While highlighting harms, guidelines support atypical antipsychotic use:  
    • Isevere aggression if risk to patient/othersBalance benefit versus risk of death and cerebrovascular events.14 
    • Target agitation without sedation.15 

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  • G. Michael Allan MD CCFP
  • Jamil Ramji BSc BSP ACPR
  • Joey Ton PharmD

1. Ma H, Huang Y, Cong Z, et al. J Alzheimers Dis. 2014; 42(3):915-37.

2. Ballard C, Waite J. Cochrane Database Syst Rev. 2006; 1:CD003476.

3. Yury CA, Fisher JE. Psychother Psychosom. 2007; 76(4):213-8.

4. Schneider LS, Dagerman K, Insel PS. Am J Geriatr Psychiatry. 2006; 14:191-210.

5. Cheung G, Stapelberg J. N Z Med J. 2011; 124:39-50.

6. Lonergan E, Luxenberg J, Colford J. Cochrane Database Syst Rev. 2002; 2:CD002852.

7. Rosenberg PB, Drye LT, Porsteinsson AP, et al. Int Psychogeriatr. 2015; 27:2059-67.

8. Campbell N, Ayub A, Boustani MA, et al. Clin Interv Aging. 2008; 3(4):719-28.

9. Seitz DP, Adunuri N, Gill SS, et al. Cochrane Database Syst Rev. 2011; 2:CD008191.

10. Martinon-Torres G, Fioravanti M, Grimley EJ. Cochrane Database Syst Rev. 2004; 4:CD004990.

11. Lonergan E, Luxenberg J. Cochrane Database Syst Rev. 2009; 3:CD003945.

12. McCracken R, Allan GM. Tools for Practice. Available at: Last Accessed: October 3, 2017.

13. Allan GM, Behn Smith D. Tools for Practice. Available at: Last Accessed: October 3, 2017.

14. Toward Optimized Practice. Cognitive Impairment Clinical Practice Guideline; 2017. Available at: Last Accessed: September 28, 2017.

15. National Institute for Health and Care Excellence. Dementia: supporting people with dementia and their carers in health and social care; 2016. Available at: Last Accessed: September 28, 2017.

Authors do not have any conflicts of interest to declare.