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Clinical Trial
. 2025 May;31(5):1586-1591.
doi: 10.1038/s41591-025-03569-y. Epub 2025 Mar 25.

Escitalopram for agitation in Alzheimer's dementia: a randomized controlled phase 3 trial

Tarek K Rajji  1   2   3 , Sheriza N Baksh  4 , David M Shade  4 , Zahinoor Ismail  5 , Amer M Burhan  6   7 , Hamid R Okhravi  8 , Prasad R Padala  9 , Paul B Rosenberg  10 , Lon S Schneider  11 , Anton P Porsteinsson #  12 , Constantine G Lyketsos #  10 ; S-CitAD Research Group
Affiliations
Clinical Trial

Escitalopram for agitation in Alzheimer's dementia: a randomized controlled phase 3 trial

Tarek K Rajji et al. Nat Med. 2025 May.

Abstract

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 .

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Conflict of interest statement

Competing interests: T.K.R. has received research support from Brain Canada, the Brain and Behavior Research Foundation, the BrightFocus Foundation, the Canada Foundation for Innovation, the Canada Research Chair, the Canadian Institutes of Health Research (CIHR), the Centre for Aging and Brain Health Innovation, the National Institutes of Health (NIH), the Ontario Ministry of Health and Long-Term Care, the Ontario Ministry of Research and Innovation and the Weston Brain Institute. T.K.R. also received investigator-initiated study in-kind equipment support from Newronika and in-kind research online accounts from Scientific Brain Training Pro and participated in 2021 and 2022 in an advisory activity for Biogen Canada. As of 1 September 2023, T.K.R. was an ex officio member of the Board of Trustees of the Centre for Addiction and Mental Health (CAMH) in his role as Chair of the Medical Advisory Committee at CAMH in 2023 and 2024. T.K.R. is also an inventor on United States Provisional Patent 17/396,030 that describes cell-based assays and kits for assessing serum cholinergic receptor activity. S.N.B. and D.M.S. received funding from the NIH, the American Lung Association, the State of Maryland and the US Department of Defense (DOD) (Defense Health Agency) during the period of S-CitAD. Z.I. has received research funding from the Alzheimer’s Drug Discovery Foundation, the Canadian Consortium on Neurodegeneration in Aging, the CIHR, Brain Canada, the NIH and the Weston Foundation and has served as an advisor/consultant for Eisai, Eli Lilly, Lundbeck, Novo Nordisk, Otsuka and Roche. A.M.B. is a contracting investigator with Headlands Research (Toronto Memory Program); served as a paid consultant to HealthTech Connex, Atheneum Partners; served on advisory boards and speakers’ bureaus for Eisai, Avanir, Janssen, Roche, Otsuka/Lundbeck and Boehringer Ingelheim Canada; and received research grants from the National Institute on Aging (NIA)/NIH, the CIHR, the National Research Council, Brain Canada, Centre for Aging + Brain Health Innovation, the Ontario Shores Centre, Western University, the Lawson Health Research Institute, St Josephʼs Health Care London and the Weston Foundation. H.R.O. has received research grants from the NIH, the Alzheimer’s Clinical Trials Consortium, the Alzheimer’s Association, Eisai, Biogen, Optina Diagnostics, Woolsey Pharmaceuticals, the American College of Radiology and Ananda Hemp. He has received honoraria from Biogen and Optina Diagnostics. P.R.P. received research support from the Office of Research Development, the US Department of Veterans Affairs, the Alzheimer’s Association and the NIH. P.B.R. has received research grants from the NIA, the Alzheimer’s Clinical Trials Consortium, the Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease, Eisai, Functional Neuromodulation Ltd and Eli Lilly; and honoraria from Eli Lilly, Guidepoint, GLG, Leerink, Cerevel, Cerevance, BioXcel, Sunovion, Acadia, Medalink, Novo Nordisk, Noble Insights, TwoLabs, Otsuka, Lundbeck, Acadia, MEDACorp, ExpertConnect, HMP Global, Sinaptica, Synaptogenix and Neurology Week. P.B.R. has received grant support from the NIA (AGRO1054771 (CRD), AGRO1050515 (dronabinol) and AGRO1046543 (ADMET II)). L.S.S. reports, within a 36-month timeframe, grants from the NIH (R01 AG054434 (Delivery of essential fatty acids to the brain in Alzheimer’s disease), P30 AG066530 (USC ADRC), R01 AG062687, R01 AG051346, R01 AG055444, P01 AG02350, R01 AG053267 (DIAN-TU), R01 AG074983 (Aβ and tau vaccines) and R01 AG063826 (State of California CADC 15-10291)); grants and personal fees from Eli Lilly/Avid; grants and personal fees from Roche/Genentech; grants/contracts from Eisai, Biogen and Biohaven; grants from Washington University in St Louis/NIA DIAN-TU; grants from UC San Diego ADCS; personal fees from Neurim (Israel), Cognition Therapeutics, Corium, Immunobrain Checkpoint Ltd (Israel), Alpha Cognition, BioVie, Lexeo, Lighthouse, AC Immune (Switzerland), Athira, GW Research (UK, Jazz, USA), Merck, Otsuka (USA), Pharmatrophix, Linus Health, Lundbeck, Novo Nordisk, Muna (Denmark), ONO Ltd and Vivli.org, all outside the submitted work; and support from the Della Martin Foundation endowment. A.P.P. reports personal fees from Acadia Pharmaceuticals, Athira, Biogen, Bristol Myers Squibb, Cognitive Research Corporation, Eisai, IQVIA, Lundbeck, Novartis, ONO Pharmaceuticals, WCG, WebMD and Xenon and grants to his institution from Alector, Athira, Biogen, Cassava, Eisai, Eli Lilly, Genentech/Roche, Vaccinex, the NIA, the National Institute of Mental Health and the DOD. He is a member of the scientific advisory boards of Alzheon, Athira and Cognition Therapeutics. C.G.L. has received research funding from the NIH, the Alzheimerʼs Association, NFL Benefits, Functional Neuromodulation Ltd, the BrightFocus Foundation and private donors. He has served as a paid consultant or advisor for AstraZeneca, GlaxoSmithKline, Eisai, Novartis, Forest, Supernus, Adlyfe, Takeda, Wyeth, Lundbeck, Merz, Eli Lilly, Pfizer, Genentech, Elan, the NFL Players Association, the NFL Benefits Office, Zinfandel, Bristol Myers Squibb, AbbVie, Janssen, Orion, Servier, Astellas, SVB Leerink, Roche, Avanir, Karuna, Maplight, Axsome, GIA, GW Research Ltd, Merck, EXCIVA GmbH, Otsuka, Intra-Cellular Therapies and Medesis.

References

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