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Randomized Controlled Trial
. 2014 Jun 10;9(6):e98426.
doi: 10.1371/journal.pone.0098426. eCollection 2014.

Changes in QTc interval in the citalopram for agitation in Alzheimer's disease (CitAD) randomized trial

Lea T Drye  1 , David Spragg  2 , D P Devanand  3 , Constantine Frangakis  4 , Christopher Marano  5 , Curtis L Meinert  6 , Jacobo E Mintzer  7 , Cynthia A Munro  8 , Gregory Pelton  9 , Bruce G Pollock  10 , Anton P Porsteinsson  11 , Peter V Rabins  12 , Paul B Rosenberg  13 , Lon S Schneider  14 , David M Shade  15 , Daniel Weintraub  16 , Jerome Yesavage  17 , Constantine G Lyketsos  18 ; CitAD Research Group
Collaborators, Affiliations
Randomized Controlled Trial

Changes in QTc interval in the citalopram for agitation in Alzheimer's disease (CitAD) randomized trial

Lea T Drye et al. PLoS One. .

Abstract

Background: A Food and Drug Administration (FDA) safety communication in August 2011 warned that citalopram was associated with a dose dependent risk of QT prolongation and recommended dose restriction in patients over the age of 60 but did not provide data for this age group.

Methods: CitAD was a randomized, double-masked, placebo-controlled, multicenter clinical trial for agitation in Alzheimer's disease (AD). Participants were assigned to citalopram (target dose of 30 mg/day) or placebo in a 1 ∶ 1 ratio. 186 people, 181 of whom were over the age of 60, having probable AD with clinically significant agitation were recruited from September 2009 to January 2013. After the FDA safety communication about citalopram, ECG was added to the required study procedures before enrollment and repeated at week 3 to monitor change in QTc interval. Forty-eight participants were enrolled after enhanced monitoring began.

Results: Citalopram treatment was associated with a larger increase in QTc interval than placebo (difference in week 3 QTc adjusting for baseline QTc: 18.1 ms [95% CI: 6.1, 30.1]; p = 0.004). More participants in the citalopram group had an increase ≥ 30 ms from baseline to week 3 (7 in citalopram versus 1 in placebo; Fisher's exact p = 0.046), but only slightly more in the citalopram group met a gender-specific threshold for prolonged QTc (450 ms for males; 470 ms for females) at any point during follow-up (3 in citalopram versus 1 in placebo, Fisher's exact p = 0.611). One of the citalopram participants who developed prolonged QTc also displayed ventricular bigeminy. No participants in either group had a cardiovascular-related death.

Conclusion: Citalopram at 30 mg/day was associated with improvement in agitation in patients with AD but was also associated with QT prolongation.

Trial registration: ClinicalTrials.gov NCT00898807.

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Conflict of interest statement

Competing Interests: The authors have read the journal's policy and have the following conflicts. Dr. Porsteinsson reports receiving research funding from Avanir, Baxter, BMS, Elan, EnVivo, Genentech/Roche, Janssen Alzheimer Initiative, Merck, Pfizer, Toyama, Medivation, National Institutes of Health (NIH), and Department of Defense; is a paid consultant for Elan, Janssen Alzheimer Initiative, and Pfizer; is a board member on Data Safety and Monitoring Boards for Quintiles, Functional Neuromodulation, and New York State Psychiatric Institute; participated on a Speaker's Bureau for Forest and developed educational presentations for CME, inc. Dr. Pollock reports being a board member on Data Safety and Monitoring Boards for Lundbeck Canada; is a paid consultant for Wyeth; has received travel and accommodation expenses from Lundbeck International Neuroscience Foundation. Dr. Devanand reports receiving grant funding from the NIH and Eli Lilly. Dr. Ismail reports being paid for lectures by Calgary Foothills Primary Care Network, Calgary West Central Primary Care Network, Canadian Conference on Dementia, Alberta College of Family Physicians, and University of British Columbia and is a paid consultant for Astra Zeneca, Janssen, Lundbeck, Otsuka, Pfizer, and Sunovion. Dr. Meinert reports receiving grant funding from the NIH. Dr. Mintzer reports receiving research funding from Accera, Avanir, Baxter, Elan, Eli Lilly, F. Hoffmann-La Roche, Genentech, Janssen Alzheimer Initiative, Merck, Novartis, Pfizer, Takeda Global Research & Development Center, Wyeth, and NIH; he is employed by Roper St. Francis Healthcare, Medical University of South Carolina, Ralph H. Johnson VA Medical Center, and NeuroQuest and is founder of BioPharma Connex. Dr. Munro reports receiving grant funding from the NIH; being paid for expert testimony from various law firms, Office of Federal Public Defender, and US Attorney's Office; and being paid for lectures for Episcopal Ministries. Dr. Rabins reports being paid for legal testimony from Janssen. Dr. Rosenberg reports receiving research funding from Elan, Eli Lilly, Merck, and Functional Neuromodulation, Inc.; is a paid consultant for Janssen and Pfizer; has developed educational presentations for Eli Lilly. Dr. Schneider reports receiving grant funding from the NIH; is a paid consultant for Forest Laboratories, Eli Lilly, Astra Zeneca, Johnson and Johnson, Bristol Myers Squibb and Otsuka, and Abbott and Abbvie. Dr. Lyketsos reports receiving grant funding from the NIH; is a paid consultant for Avanir, BMS, Elan, Eli Lilly, Genentech, GSK, Janssen, Novartis, NFL, and Pfizer; reports being a board member on Data Safety and Monitoring Boards for Eli Lilly and Janssen; and receiving royalties from Oxford University Press. Drs. Drye, Spragg, Frangakis, Marano, Pelton, Weintraub, Yesavage and Mr. Shade report no conflicts of interest.

Figures

Figure 1
Figure 1. Participant flow* related to ECG monitoring.
Figure 2
Figure 2. Baseline and week 3 QTc.
Figure 3
Figure 3. Change in QTc by baseline QTc and treatment group.
Figure 4
Figure 4. ECG of patient with prolonged QTc and bigeminy.
See this image and copyright information in PMC

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