REVIEW OF: Rajji TK et al, Nat Med 2025;31(5):1586–1591
STUDY TYPE: RCT

Citalopram works for agitation in Alzheimer’s disease (AD), but it comes with baggage: FDA dosing limits in older adults and QT prolongation concerns tied to its R-enantiomer. Escitalopram, which is the pure S-enantiomer, looked like a cleaner alternative. This trial put that idea to the test.

In this double-blind multicenter trial, 173 adults with AD and significant agitation who hadn’t responded to three weeks of a structured psychosocial intervention were randomized to escitalopram (up to 15 mg/day) or placebo, both continuing the psychosocial intervention for 12 weeks. The primary outcome was clinically meaningful improvement in agitation, rated as moderate or marked on a global impression scale at 12 weeks.

Escitalopram didn’t deliver. About 35% of patients taking it showed meaningful improvement, compared to 27% on placebo, a difference that was not statistically significant and far short of the 40% response seen with citalopram in an earlier trial. No secondary measures showed a significant benefit by week 12. Escitalopram also produced more QT prolongation, more falls, and more diarrhea than placebo.

CARLAT TAKE
Escitalopram turned out to be less effective, not cleaner. It still prolonged QT, caused more falls, and didn’t beat placebo on the primary outcome. Although the trial was underpowered, post-hoc analysis showed that over 1,000 patients would be needed to detect the observed effect, which raises the question of whether such an effect would be clinically meaningful. For agitation in AD when a medication is warranted, citalopram remains the better-supported SSRI option. Keep the dose at or below 20 mg to stay within FDA guidance, and monitor for QT prolongation.