medwireNews: Escitalopram does not significantly reduce agitation in patients with Alzheimer disease (AD) who have failed to respond to psychosocial intervention (PSI), and may be associated with cardiac conduction delays, suggests the S-CitAD study published in Nature Medicine.
The investigators therefore warn against use of the selective serotonin reuptake inhibitor (SSRI) as an alternative to the SSRI citalopram for treating agitation in AD.
While citalopram showed efficacy for treating AD agitation in the previously published CitAD trial, the authors explain that it is “associated with cognitive and cardiac risks, likely due to its R-enantiomer,” so they studied escitalopram, which contains only the S-enantiomer, as a potential substitute.
Tarek Rajji (University of Texas Southwestern Medical Centre, Dallas, USA) and colleagues enrolled 173 participants from 27 community-based centers in the USA. The patients had a mean age of 78.4 years, 52% were men, all had an AD diagnosis, a Mini-Mental State Examination Telephone (MMSET) score of 3–20 points (mean 11 points), where lower scores indicate increased dementia, and significant agitation on the Neuropsychiatric Inventory–Clinician Rating (NPI-C).
After 3 initial weeks of PSI alone, nonresponders were randomly assigned to receive escitalopram 5 mg/day for 7 days, increasing to 10 mg/day for a further 7 days, and to 15 mg/day thereafter (n=84), or matching placebo (n=89). Both treatment arms continued to receive concomitant PSI involving counseling, education, and crisis support for the duration of the study.
At the 12-week follow-up, a similar proportion of participants in each group achieved a moderate or marked improvement on the 7-point modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC; scores of 1 or 2), at rates of 34.5% for those receiving escitalopram versus 27.0% for those receiving placebo, giving a nonsignificant unadjusted risk difference.
In addition, there was no significant difference between the two groups for secondary endpoints after 3, 6, and 12 weeks of treatment, including improvement in mean scores on the Activities of Daily Living, MMSET, and NPI-C agitation and aggression domains, or the 88-point Zarit Burden Interview scale that measures caregiver burden.
The only exception was the combined NPI-C agitation and aggression domain score at 3 weeks, which was significantly improved with escitalopram compared with placebo (mean 12.4 vs 15.8). This “is consistent with an augmenting effect of escitalopram when PSI is not sufficient,” they say. However, the difference converged by week 6, which the authors say “contrasts with CitAD where the separation between [citalopram] and placebo increased over time, in particular late in the study.”
Overall, there were 390 adverse events (AEs) in the escitalopram group compared with 410 in the placebo group. Escitalopram-treated patients were significantly more likely than those given placebo to experience falls (9.2 vs 4.6%) and diarrhea (13.8 vs 6.6%), but there was no significant difference between the two groups when the team assessed “get-up and go” scores.
There were a similar number of serious AEs in the escitalopram and placebo groups, namely 16 vs 22, including one and four fatal events, respectively.
Of note, the team found escitalopram was associated with a significantly higher incidence of corrected QT interval prolongation when measured using Bazett’s formula and predefined cutoffs of above 450 ms for women and above 470 ms for men. Among men, the rates were 7.2% versus 2.5% for those receiving escitalopram and placebo, respectively, and 3.1% versus 0.8% among women.
Rajji and team observe that escitalopram appears to “have fewer adverse cognitive effects than citalopram,” which was previously associated with a decline in MMSE scores. However, they say that their “results provide no reason to think that escitalopram is superior to citalopram and, in fact, it might be inferior.”
The researchers therefore suggest that, considering the increased risk for AEs in their study, “citalopram should be the preferred choice over escitalopram for the treatment of agitation in AD when an SSRI is indicated.”
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Nat Med 2025; doi: 10.1038/s41591-025-03569-y
