Which drugs are best when aggressive Alzheimer’s patients need medication?

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Clinical Inquiries

Which drugs are best when aggressive Alzheimer’s patients need medication?

J Fam Pract. 2010 October;59(10):595-604

By

Brice Labruzzo Mohundro, PharmD

Karla Pope, MD, MHSA

Vincent Shaw, MD

Kristin Hitchcock, MSI

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References

1. Brodaty H, Ames D, Snowdon J, et al. Risperidone for psychosis of Alzheimer’s disease and mixed dementia: results of a double-blind, placebo-controlled trial. Int J Geriatr Psychiatry. 2005;20:1153-1157.

2. Katz IR, Jeste DV, Mintzer JE, et al. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. Risperidone Study Group. J Clin Psychiatry. 1999;60:107-115.

3. Frank L, Kleinman L, Ciesla G, et al. The effect of risperidone on nursing burden associated with caring for patients with dementia. J Am Geriatr Soc. 2004;52:1449-1455.

4. Street JS, Clark WS, Gannon KS, et al. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer’s disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group. Arch Gen Psychiatry. 2000;57:968-976.

5. Street JS, Clark WS, Kadam DL, et al. Long-term efficacy of olanzapine in the control of psychotic and behavioral symptoms in nursing home patients with Alzheimer’s dementia. Int J Geriatr Psychiatry. 2001;16(suppl 1):S62-S70.

6. US Food and Drug Administration Deaths with antipsychotics in elderly patients with behavioral disturbances. Available at: www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm053171.htm. Accessed October 20, 2009.

7. Schneider LS, Dagerman KS, Insel PI. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005;294:1934-1943.

8. Gill SS, Bronskill SE, Normand ST, et al. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med. 2007;146:775-786.

9. Pollock BG, Mulsant BH, Rosen J, et al. A double-blind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia. Am J Geriatr Psychiatry. 2007;15:942-952.

10. Tariot PN, Erb R, Podgorski CA, et al. Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J Psychiatry. 1998;155:54-61.

11. Sival RC, Jaff mans PM, Fransen PA, et al. Sodium valproate in the treatment of aggressive behaviour in patients with dementia: a randomized, placebo-controlled clinical trial. Int J Geriatr Psychiatry. 2002;17:579-585.

12. Sival RC, Duivenvoorden HJ, Jansen PA, et al. Sodium valproate in aggressive behaviour in dementia: a twelve-week open label follow-up study. Int J Geriatr Psychiatry. 2004;19:305-312.

13. Herrmann N, Lanctot KL, Rothenburg LS, et al. A placebo-controlled trial of valproate for agitation and aggression in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2007;23:116-119.

14. Treatment of agitation in older persons with dementia. The Expert Consensus Guideline Series. Postgrad Med. 1998 March; Spec No:1-88.

15. Rabins PV, Blacker D, Rovner BW, et al. Treatment of patients with Alzheimer’s disease and other dementias, 2nd ed. Available at: www.psychiatryonline.com/pracGuide/pracGuideTopic_3.aspx. Accessed October 18, 2009.

EVIDENCE-BASED ANSWER

ATYPICAL ANTIPSYCHOTICS ARE EFFECTIVE; so are selective serotonin reuptake inhibitors (SSRIs), and they may be safer. Atypical antipsychotics are an effective short-term (6-12 weeks) treatment for aggressive behavior in patients with Alzheimer’s disease because they consistently decrease aggression scores (strength of recommendation [SOR]: A, multiple randomized controlled trials [RCTs]). However, evidence of drug-related deaths in patients taking these drugs mandates weighing the benefits against the risks. SSRIs may be a safer, effective alternative (SOR: B, limited studies).

Evidence for the efficacy of antiepileptic agents is conflicting (SOR: C, inconsistent patient-oriented evidence). Valproate is ineffective for treating aggression (SOR: C, very small RCT).

No data exist to guide long-term medication use. All available studies lasted no longer than 12 weeks.

Nonpharmacologic therapy should be the first-line treatment for aggression in patients with Alzheimer’s disease. Consider drug therapy for patients who pose an imminent threat to themselves or others.

Evidence summary

Psychotic symptoms, including aggression, in patients with dementia are a leading cause of nursing home placement and pharmacologic treatment. RCTs have demonstrated the efficacy of atypical antipsychotics in aggressive nursing home patients.

Risperidone significantly reduces aggression
An RCT comparing risperidone with placebo in 345 patients found that low-dose risperidone (mean 0.95 mg/d) significantly improved aggression scores (number needed to treat [NNT][H11005]4; P<.001). Serious adverse events included injury, cerebrovascular events, pneumonia, and accidental overdose (number needed to harm [NNH][H11005]13).¹ Other RCTs also have found risperidone to be effective in reducing aggressive behavior.^2,3

Olanzapine is effective and well tolerated
Researchers have also studied olanzapine, another atypical antipsychotic. A 6-week RCT of 206 elderly nursing home patients with Alzheimer’s disease and psychotic or behavioral symptoms found that low-dose olanzapine (5 or 10 mg/d) decreased agitation and aggression scores (olanzapine 5 mg: NNT=5; olanzapine 10 mg: NNT=6) compared with placebo. Commonly reported adverse effects included somnolence (5 mg: NNH=5; 10 mg: NNH=5) and gait disturbance (5 mg: NNH=6; 10 mg: NNH=8).⁴ An open-label follow-up study also found low-dose olanzapine to be well tolerated and effective in decreasing agitation and aggression scores.⁵

FAST TRACK

Atypical antipsychotics are an effective short-term treatment for aggressive behavior.

Weigh the benefits against the risks
The US Food and Drug Administration issued a public health advisory regarding increased mortality risk after reviewing RCTs that evaluated atypical antipsychotics in patients with dementia.⁶ A meta-analysis of 15 RCTs (N=5110) that studied olanzapine, aripiprazole, risperidone, and quetiapine in patients with dementia demonstrated a small, but increased risk of death associated with their use when compared with placebo (3.5% vs 2.3%; odds ratio=1.54; 95% confidence interval [CI], 1.06-2.23; P=.02; NNH= 83).⁷

A population-based (community and long-term care facilities), retrospective cohort study of atypical and conventional antipsychotics involving 27,259 matched pairs also suggested an increased risk of death. Thirty days after beginning an atypical antipsychotic medication, increased mortality was noted when compared with no antipsychotic use in both the community cohort (adjusted hazard ratio [AHR]=1.31 [95% CI, 1.02-1.70]; NNH=500) and the long-term care cohort (AHR=1.55 [95% CI, 1.15-2.07]; absolute risk difference=1.2 percentage points; NNH=83). Conventional antipsychotics were associated with higher rates of death than atypical antipsychotics (absolute risk difference=2.6 percentage points in the community group [NNH=38] and 2.2 percentage points in the long-term care groups [NNH=45]).⁸

SSRIs may be an alternative
An RCT comparing citalopram and risperidone over 12 weeks in 103 patients with dementia demonstrated similar efficacy for the 2 drugs in treating agitation. Patients receiving citalopram experienced fewer adverse effects than those receiving risperidone.⁹ The study suggests that SSRIs may be an alternative to atypical antipsychotics.

Carbamazepine helps, valproate doesn’t
Evidence regarding the use of antiepileptic medications is conflicting. One RCT of 51 patients found carbamazepine 300 mg daily to be efficacious for short-term control of agitation with good safety and tolerability. Six weeks after beginning the study, Overt Aggression Scale scores decreased 6.7 points for carbamazepine compared with 1.9 points for placebo (P=.008). Adverse effects, including ataxia, drowsiness, postural instability, rash, weakness, and disorientation, were more common in the carbamazepine group than the placebo group (absolute risk increase=30%; NNH=3).¹⁰

Evidence-based answers from the Family Physicians Inquiries Network