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Escitalopram for agitation in Alzheimer's dementia: a randomized controlled phase 3 trial
Rajji TK, Baksh SN, Shade DM, Ismail Z, Burhan AM, Okhravi HR, Padala PR, Rosenberg PB, Schneider LS, Porsteinsson AP, et al.. Nature Medicine, 2025-03-25
Topic: Amyloid, tau and blood-test diagnosis
Citalopram is effective in treating agitation in Alzheimer's dementia (AD), but it is associated with cognitive and cardiac risks, likely due to its R-enantiomer. Escitalopram, the S-enantiomer, may be an alternative. In this double-masked randomized (1:1) placebo-controlled trial, we assessed the efficacy and safety of escitalopram in treating agitation in AD after failure of a psychosocial intervention (PSI). Assessments occurred at enrollment, post-PSI (baseline) and at 3, 6, 9 and 12 weeks post-baseline. Settings were 27 community-based centers. The target randomization sample was 392 participants. Participants were adults with AD, a Mini-Mental State Examination Telephone score of 3-20 and significant agitation. PSI non-responders received escitalopram (up to 15 mg per day) or placebo for 12 weeks while continuing PSI. The outcome was the proportion of participants with clinically significant improvement in agitation from baseline at 12 weeks. In total, 173 participants were randomized (84 escitalopram versus 89 placebo; mean ± s.d. age = 78.4 ± 8.7 years; 90 men (52.0%); 127 White (73.4%)). The unadjusted risk difference at 12 weeks was 0.08 (95% confidence interval: -0.21, 0.06). Drug-related QT interval prolongation was observed. Although the randomized sample was smaller than planned, escitalopram was not effective in treating agitation in AD and was associated with cardiac conduction delays. Clinicians need to be cautious in recommending escitalopram as an alternative to citalopram for this condition. ClincialTrials.gov identifier: NCT03108846 .
Key findings
- Citalopram is effective in treating agitation in Alzheimer's dementia (AD), but it is associated with cognitive and cardiac risks, likely due to its R-enantiomer.
- Participants were adults with AD, a Mini-Mental State Examination Telephone score of 3-20 and significant agitation.
- The outcome was the proportion of participants with clinically significant improvement in agitation from baseline at 12 weeks.
- In total, 173 participants were randomized (84 escitalopram versus 89 placebo; mean ± s.d. age = 78.4 ± 8.7 years; 90 men (52.0%); 127 White (73.4%)).
- Although the randomized sample was smaller than planned, escitalopram was not effective in treating agitation in AD and was associated with cardiac conduction delays.
Why it matters
In this trial, escitalopram was not effective in treating agitation in Alzheimer's dementia and was associated with cardiac risks. The randomized sample was smaller than planned.
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Study details
- Study designphase-3-trial
- Participants173
- Effect sizeRisk difference for clinically significant improvement 0.08 (95% CI -0.21 to 0.06)
- Evidence strengthNull-result
Limitations
Under-enrolled (173 of a planned 392), reducing power; 12-week duration; participants had already failed a psychosocial intervention so may represent harder-to-treat agitation.
How this study scored 74/100
Published in a top-tier journal, and it is a large phase 3 trial. We have no data on free to read, so that was left out: it earned 73 of the 98 points we could judge it on, which is 74 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature Medicine) |
| Journal's citation record | 4 / 4 | Nature Medicine: journal h-index 763 (OpenAlex, 2026-10-29) |
| Study design | 11 / 12 | A large phase 3 trial |
| Strength of evidence | 3 / 5 | Rated “null-result” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 2 / 4 | 173 participants |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 1 / 2 | Randomised (as stated in the record) |
| Times cited | 3 / 7 | Cited 16 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 5.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 4 / 6 | Cited 10.2× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 2 / 4 | Cited 16 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Constantine George Lyketsos: h-index 130 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Johns Hopkins University: institution h-index 2,306 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 17 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40133524) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 73 / 98 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 73 of the 98 points we could judge it on is 74 out of 100. |
| Total | 74 / 100 | — |
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Read the original
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Rajji, T. K., Baksh, S. N., Shade, D. M., Ismail, Z., Burhan, A. M., Okhravi, H. R., et al. (2025). Escitalopram for agitation in Alzheimer's dementia: a randomized controlled phase 3 trial. Nature Medicine. https://doi.org/10.1038/s41591-025-03569-y
Vancouver
Rajji TK, Baksh SN, Shade DM, Ismail Z, Burhan AM, Okhravi HR, et al. Escitalopram for agitation in Alzheimer's dementia: a randomized controlled phase 3 trial. Nature Medicine. 2025. doi:10.1038/s41591-025-03569-y. PMID: 40133524.
BibTeX
@article{rajji2025-40133524,
author = {Rajji, T. K. and Baksh, S. N. and Shade, D. M. and Ismail, Z. and Burhan, A. M. and Okhravi, H. R. and Padala, P. R. and Rosenberg, P. B. and Schneider, L. S. and Porsteinsson, A. P. and others},
title = {{Escitalopram for agitation in Alzheimer's dementia: a randomized controlled phase 3 trial}},
journal = {Nature Medicine},
year = {2025},
doi = {10.1038/s41591-025-03569-y},
pmid = {40133524},
url = {https://doi.org/10.1038/s41591-025-03569-y}
}
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