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Am J Psychiatry. 2016 May 1;173(5):465-72. doi: 10.1176/appi.ajp.2015.15050648. Epub 2016 Jan 15.

Heterogeneity of Treatment Response to Citalopram for Patients With Alzheimer's Disease With Aggression or Agitation: The CitAD Randomized Clinical Trial.

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From the Department of Psychiatry and Behavioral Sciences and the Department of Neurology, Keck School of Medicine of University of Southern California, Los Angeles; the Department of Biostatistics, the Department of Epidemiology, and the Center for Clinical Trials and Evidence Synthesis, Johns Hopkins Bloomberg School of Public Health, Baltimore; the Division of Geriatric Psychiatry, Department of Psychiatry, New York State Psychiatric Institute and Columbia University Medical Center, New York; the Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine, Baltimore; the Clinical Biotechnology Research Institute, Roper St. Francis Healthcare, Charleston, S.C.; the Campbell Institute, Centre for Addiction and Mental Health, and the Department of Psychiatry, University of Toronto, Toronto; the Culture and Mental Health Laboratory, University of Southern California, Los Angeles; the Department of Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, N.Y.; the Biostatistics Consulting Center, Medical College of Wisconsin, Milwaukee; the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia; the Department of Veterans Affairs Health Care System, Palo Alto, Calif.; and the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford.



Pharmacological treatments for agitation and aggression in patients with Alzheimer's disease have shown limited efficacy. The authors assessed the heterogeneity of response to citalopram in the Citalopram for Agitation in Alzheimer Disease (CitAD) study to identify individuals who may be helped or harmed.


In this double-blind parallel-group multicenter trial of 186 patients with Alzheimer's disease and clinically significant agitation, participants were randomly assigned to receive citalopram or placebo for 9 weeks, with the dosage titrated to 30 mg/day over the first 3 weeks. Five planned potential predictors of treatment outcome were assessed, along with six additional predictors. The authors then used a two-stage multivariate method to select the most likely predictors; grouped participants into 10 subgroups by their index scores; and estimated the citalopram treatment effect for each.


Five covariates were likely predictors, and treatment effect was heterogeneous across the subgroups. Patients for whom citalopram was more effective were more likely to be outpatients, have the least cognitive impairment, have moderate agitation, and be within the middle age range (76-82 years). Patients for whom placebo was more effective were more likely to be in long-term care, have more severe cognitive impairment, have more severe agitation, and be treated with lorazepam.


Considering several covariates together allowed the identification of responders. Those with moderate agitation and with lower levels of cognitive impairment were more likely to benefit from citalopram, and those with more severe agitation and greater cognitive impairment were at greater risk for adverse responses. Considering the dosages used and the association of citalopram with cardiac QT prolongation, use of this agent to treat agitation may be limited to a subgroup of people with dementia.

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