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Original Investigation |

Effect of Citalopram on Agitation in Alzheimer Disease:  The CitAD Randomized Clinical Trial

Anton P. Porsteinsson, MD1; Lea T. Drye, PhD2; Bruce G. Pollock, MD, PhD3; D. P. Devanand, MD4,5; Constantine Frangakis, PhD2; Zahinoor Ismail, MD6; Christopher Marano, MD7; Curtis L. Meinert, PhD2; Jacobo E. Mintzer, MD, MBA8; Cynthia A. Munro, PhD7; Gregory Pelton, MD4; Peter V. Rabins, MD7; Paul B. Rosenberg, MD7; Lon S. Schneider, MD9; David M. Shade, JD2; Daniel Weintraub, MD10; Jerome Yesavage, MD11,12; Constantine G. Lyketsos, MD, MHS7 ; for the CitAD Research Group
[+] Author Affiliations
1University of Rochester School of Medicine and Dentistry, Rochester, New York
2Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
3Campbell Institute, CAMH, University of Toronto, Toronto, Ontario, Canada
4Division of Geriatric Psychiatry, New York State Psychiatric Institute, New York
5College of Physicians and Surgeons of Columbia University, New York, New York
6Departments of Psychiatry and Neurology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
7Johns Hopkins Bayview and Johns Hopkins School of Medicine, Baltimore, Maryland
8Clinical Biotechnology Research Institute, Roper St Francis Healthcare, Charleston, South Carolina
9University of Southern California Keck School of Medicine, Los Angeles
10Perelman School of Medicine at the University of Pennsylvania, Philadelphia
11Stanford University School of Medicine, Stanford, California
12VA Palo Alto Health Care System, Stanford, California
JAMA. 2014;311(7):682-691. doi:10.1001/jama.2014.93.
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Importance  Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer disease. Pharmacological treatment options, including antipsychotics are not satisfactory.

Objective  The primary objective was to evaluate the efficacy of citalopram for agitation in patients with Alzheimer disease. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability.

Design, Setting, and Participants  The Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable Alzheimer disease and clinically significant agitation from 8 academic centers in the United States and Canada from August 2009 to January 2013.

Interventions  Participants (n = 186) were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks. Dosage began at 10 mg per day with planned titration to 30 mg per day over 3 weeks based on response and tolerability.

Main Outcomes and Measures  Primary outcome measures were based on scores from the 18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). Other outcomes were based on scores from the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory (NPI), ability to complete activities of daily living (ADLs), caregiver distress, cognitive safety (based on scores from the 30-point Mini Mental State Examination [MMSE]), and adverse events.

Results  Participants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was −0.93 (95% CI, −1.80 to −0.06), P = .04. Results from the mADCS-CGIC showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given CGIC category) of 2.13 (95% CI, 1.23-3.69), P = .01. Participants who received citalopram showed significant improvement on the CMAI, total NPI, and caregiver distress scores but not on the NPI agitation subscale, ADLs, or in less use of rescue lorazepam. Worsening of cognition (−1.05 points; 95% CI, −1.97 to −0.13; P = .03) and QT interval prolongation (18.1 ms; 95% CI, 6.1-30.1; P = .01) were seen in the citalopram group.

Conclusions and Relevance  Among patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of citalopram may limit its practical application at the dosage of 30 mg per day.

Trial Registration  clinicaltrials.gov Identifier: NCT00898807

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Figure 1.
Participant Flow in Randomization to Citalopram vs Placebo for Agitation in Alzheimer Disease

Data for the individuals who were initially screened for eligibility, those excluded, and the reasons for exclusion were not available.aData from participants were included in the analysis in the originally assigned treatment group, regardless of treatment adherence.bComparisons comprising the primary outcomes: (1) difference in week-9 scores between citalopram and placebo on the Neurobehavioral Rating Scale-agitation subscale (NBRS-A) calculated using mixed-effects regression; and (2) ratings on the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC) at week 9 calculated using proportional odds regression.cNBRS slope model included data from all randomized participants. For the mADCS-CGIC sensitivity analyses, outcomes were multiply imputed.dTwo participants in the placebo group underwent the week-9 visit but the mADCS-CGIC was not administered.

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Figure 2.
Neurobehavioral Rating Scale (NBRS)-Agitation Subscale

Higher NBRS scores indicate more severe symptoms. The horizontal bar inside the boxes indicates the median, the square in the boxes indicates the mean, and the lower and upper ends of the boxes are the first and third quartiles. The whiskers indicate values within 1.5 × the interquartile range from the upper or lower quartile (or the minimum and maximum if within 1.5 × the interquartile range of the quartiles) and data more extreme than the whiskers are plotted individually as outliers.

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