Clinical Question

Which medications are effective at decreasing agitation in patients with dementia?

Evidence-Based Answer

Selective serotonin reuptake inhibitors (SSRIs) and risperidone (Risperdal) are moderately effective at decreasing agitation in all types of dementia. (Strength of Recommendation [SOR]: A, based on meta-analysis.) Olanzapine (Zyprexa) and risperidone reduce dementia-related agitation much longer than placebo. (SOR: B, based on one high-quality randomized controlled trial [RCT].) Dextromethorphan/quinidine (Nuedexta) may be effective at reducing agitation in patients with dementia. (SOR: B, based on one high-quality RCT cited in meta-analysis.)¹

Evidence Summary

A 2018 meta-analysis examining medications used to alleviate agitation in all types of dementia included 36 RCTs with a total of 5,585 participants (mean age = 81.8 years ± 4.9 years; 69.1% female).¹ The primary outcome was a 50% reduction in baseline agitation at eight weeks. Twenty individual medications and one combination medication were included in the analyses. Risperidone (odds ratio [OR] = 1.96; 95% CI, 1.49 to 2.59; number needed to treat [NNT] = 6) and SSRIs as a class (OR = 1.61; 95% CI, 1.02 to 2.53; NNT = 25) were more effective than placebo, although no individual SSRI reached statistical significance. Dextromethorphan/quinidine was also more effective than placebo (OR = 3.04; 95% CI, 1.63 to 5.66; NNT = 5), but it was evaluated in only one RCT.

A 2011 Cochrane review assessed the safety and effectiveness of antidepressants for agitation in adults who had one of several different types of dementia, analyzing nine RCTs with a total of 692 patients.² Five trials compared SSRIs (i.e., sertraline [Zoloft], citalopram [Celexa], fluoxetine [Prozac], and fluvoxamine) with placebo over periods of 17 days to 12 weeks. SSRIs were more effective than placebo and no less safe than placebo or antipsychotics. (SOR = A, based on meta-analysis.) Two trials measured changes in Cohen-Mansfield Agitation Inventory scores (assessing 29 behaviors, each scored by an observer as 1 point [never] to 7 points [multiple occurrences per hour]) and found a slight yet statistically significant improvement with SSRIs compared with placebo (mean difference of improvement = −0.89 points across all behaviors; 95% CI, −1.22 to −0.57). Four trials assessed the rates of withdrawal because of adverse effects from SSRIs vs. placebo. They showed no difference (relative risk = 1.07; 95% CI, 0.55 to 2.11). One trial comparing citalopram and risperidone measured change on the Neurobehavioral Rating Scale (a 28-item observer-rated scale using seven gradations ranging from not present [1 point] to extremely severe [7 points]) and showed similar effectiveness (mean difference = −0.53 points; 95% CI, −2.37 to 1.31) and no significant difference in withdrawal because of adverse effects.

A 2017 RCT with 75 nursing home residents who had Alzheimer-type dementia and were 60 years or older at diagnosis measured the effectiveness and safety of citalopram (30 ± 5.8 mg per day) relative to quetiapine (Seroquel) and olanzapine, with 25 patients per group.³ The interventions were equally effective in treating agitation in patients with Alzheimer-type dementia and citalopram was associated with fewer adverse outcomes than quetiapine and olanzapine. (SOR = B, based on one medium-quality RCT.) At 24 weeks, there were no significant improvements in agitation between citalopram and quetiapine as measured by two agitation scales (i.e., the Neuropsychiatric Inventory [NPI] scale: regression coefficient = 0.022; 95% CI, −0.093 to 0.137; P = .882 and the modified Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change [mADCS-CGIC] scale: OR = 1.00; 95% CI, 0.92 to 1.07; P = .935), or between citalopram and olanzapine (NPI scale: regression coefficient = −0.041; 95% CI, −0.068 to 0.036; P = .409 and mADCS-CGIC scale: OR = 0.98; 95% CI, 0.86 to 1.20; P = .849). The NPI scale assesses 12 items, each with a score of 0 to 12, with higher scores indicating worsening agitation. At baseline, NPI mean subscale scores for the trial participants in the citalopram, quetiapine, and olanzapine arms were 9.7 ± 2.1, 9.6 ± 2.0, and 9.7 ± 2.2, respectively; at 24 weeks, mean subscale scores improved by −6.5 ± 2.5, −6.6 ± 2.4, and −6.0 ± 2.0, respectively. The mADCS-CGIC score ranges from 1 to 7, with higher numbers correlating with worsening function. Improvement was defined as a mADCS-CGIC score of 1 or 2 at week 24; for the citalopram, quetiapine, and olanzapine arms, improvement was noted for 88.0%, 87.0%, and 91.3% of participants, respectively. Patients treated with citalopram had fewer falls than those treated with olanzapine (OR = 0.81; 95% CI, 0.68 to 0.91; P = .012), less orthostatic hypotension than those taking quetiapine (OR = 0.81; 95% CI, 0.68 to 0.97; P = .032) and olanzapine (OR = 0.80; 95% CI, 0.66 to 0.95; P = .020), and fewer hospitalizations than those who were given quetiapine (OR = 0.92; 95% CI, 0.88 to 0.95; P = .016) and olanzapine (OR = 0.78; 95% CI, 0.64 to 0.92; P = .004).