Changes in QTc Interval in the Citalopram for Agitation
in Alzheimer’s Disease (CitAD) Randomized Trial
Lea T. Drye1*, David Spragg2, D. P. Devanand3, Constantine Frangakis4, Christopher Marano5,
Curtis L. Meinert6, Jacobo E. Mintzer7, Cynthia A. Munro8, Gregory Pelton9, Bruce G. Pollock10,
Anton P. Porsteinsson11, Peter V. Rabins12, Paul B. Rosenberg13, Lon S. Schneider14, David M. Shade15,
Daniel Weintraub16, Jerome Yesavage17, Constantine G. Lyketsos18, for the CitAD Research Group"
1Department of Epidemiology and Center for Clinical Trials, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America,
2Electrophysiology Laboratory, Johns Hopkins Hospital and Johns Hopkins Bayview Medical Center, Baltimore, Maryland, United States of America, 3Division of Geriatric
Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America, 4Department of Biostatistics, Johns Hopkins
Bloomberg School of Public Health, Baltimore, Maryland, United States of America, 5Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School
of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, Maryland, United States of America, 6Departments of Epidemiology and Biostatistics, Johns Hopkins
Bloomberg School of Public Health, Baltimore, Maryland, United States of America, 7Clinical Biotechnology Research Institute, Roper St. Francis Healthcare, Department of
Health Studies, Medical University of South Carolina, Ralph H. Johnson VA Medical Center, Charleston, South Carolina, United States of America, 8Departments of
Psychiatry and Behavioral Sciences and Neurology, Johns Hopkins Bayview and Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of
America, 9Division of Geriatric Psychiatry, New York State Psychiatric Institute, College of Physicians and Surgeons of Columbia University, New York, New York, United
States of America, 10Campbell Family Mental Health Research Institute, Division of Geriatric Psychiatry and Centre for Addiction and Mental Health, University of Toronto,
Toronto, Ontario, Canada, 11Alzheimer’s Disease Care, Research and Education Program (AD-CARE), University of Rochester School of Medicine and Dentistry, Rochester,
New York, United States of America, 12Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine and Johns Hopkins Hospital,
Baltimore, Maryland, United States of America, 13Department of Psychiatry and Behavioral Sciences, John Hopkins University School of Medicine and Johns Hopkins
Bayview Medical Center, Baltimore, Maryland, United States of America, 14Departments of Psychiatry, Neurology, and Gerontology, Keck School of Medicine, University of
Southern California, Los Angeles, California, United States of America, 15Departments of Medicine (Pulmonary) and Epidemiology and Center for Clinical Trials, Johns
Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America, 16Departments of Psychiatry and Neurology, Perelman School of Medicine at
the University of Pennsylvania, Parkinson’s Disease Research, Education and Clinical Center (PADRECC), Mental Illness Research, Education and Clinical Center (MIRECC),
Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania, United States of America, 17Aging Clinical Research Center, Mental Illness Research Education
and Clinical Center, Veterans Affairs Palo Alto Health Care System, Departments of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto,
California, United States of America, 18Memory and Alzheimer’s Treatment Center, Department of Psychiatry and Behavioral Sciences, Johns Hopkins Bayview and Johns
Hopkins School of Medicine, Baltimore, Maryland, United States of America
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
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
Citation: Drye LT, Spragg D, Devanand DP, Frangakis C, Marano C, et al. (2014) Changes in QTc Interval in the Citalopram for Agitation in Alzheimer’s Disease
(CitAD) Randomized Trial. PLoS ONE 9(6): e98426. doi:10.1371/journal.pone.0098426
Editor: T. Mark Doherty, Glaxo Smith Kline, Denmark
Received February 11, 2014; Accepted April 19, 2014; Published June 10, 2014
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for
any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
PLOS ONE | www.plosone.org1 June 2014 | Volume 9 | Issue 6 | e98426
Funding: Grant funding: National Institute on Aging and National Institute of Mental Health, R01AG031348. The funders had no role in study design, data collection
and analysis, decision to publish, or preparation of the manuscript.
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.
* E-mail: email@example.com
" Membership of the CitAD Research Group is provided in the Acknowledgments.
The QT interval is measured on an electrocardiogram (ECG) as
the time from the beginning of the QRS complex to the end of the
T wave and corresponds to the time from onset of ventricular
depolarization to completion of repolarization. The QT interval
shortens as heart rate increases. The QTc interval is a
standardization of the QT interval correcting for heart rate.
Many formulae have been developed for calculating the QTc
value and there is no consensus on the correct conversion [1,2] but
most formulae provide similar results for diagnosis of QT
prolongation with heart rates in the range of approximately 60–
90 beats/minute . Extreme QTc prolongation (QTc.500 mil-
liseconds) can result in electrical instability during repolarization,
increasing the risk of polymorphic ventricular tachycardia (Torsade
de pointes; TdP) and sudden cardiac death [4,5]. A review of the
literature found consistent associations between prolonged QTc
and death in high risk populations  and a meta-analysis of
observational data found that the pooled estimates support
associations between prolonged QTc and death in the general
population . Although QT prolongation can be caused by
heritable disorders in cardiac ion channel expression, numerous
marketed drugs are also known to lengthen the QT interval
(QTdrugs.org) in people without genetic abnormalities.
Citalopram is a selective serotonin reuptake inhibitor (SSRI)
antidepressant that is frequently used in older adults [8,9]. On 24
August 2011, the US Food and Drug Administration (FDA) issued
a Drug Safety Communication  regarding the dose dependent
risk of QT prolongation with citalopram. The communication was
issued because of post-marketing reports of QT prolongation and
TdP and results of an unpublished, randomized, controlled, multi-
center, double-blind, crossover study that enrolled 119 healthy,
non-depressed adults. Participants in the FDA QT study received
citalopram 20 mg/day and 60 mg/day. The mean change in QTc
interval was 8.5 milliseconds (ms) for 20 mg/day and 18.5 ms for
60 mg/day . The FDA QT study included adults aged 19 to
45 (Thomas P Laughren, personal communication). The 2011
FDA communication stated that 20 mg per day was the maximum
recommended dose for patients greater than 60 years of age ,
but this language was not changed on the FDA label for Celexa
(brand name for citalopram) at that time. The Pharmacovigilance
Working Party of the European Medicines Agency also recom-
mended the same changes to maximum dose in summaries of
product characteristics and package leaflets of citalopram products
in the EU  and these were accepted by the co-ordination
Group for Mutual Recognition and Decentralised Procedures
(CMDh) agency in October 2011 . The Medicines and
Healthcare Products Regulatory Agency (MHRA) in the UK
issued a similar advisory regarding citalopram use in December
Seven months later, on 28 March 2012, the FDA issued another
Drug Safety Communication and again updated the citalopram
labeling . The revised warning recommended that citalopram
not be used by patients who have one or more of the following
conditions: congenital long QT syndrome, bradycardia, hypoka-
lemia, hypomagnesemia, recent acute myocardial infarction, or
uncompensated heart failure. This 2012 communication accom-
panied new changes to the Celexa label, and recommended a
maximum dose of 20 mg in individuals over age 60.
Following the FDA warnings, an observational study of data
from a large New England healthcare setting also found dose-
response associations between citalopram, escitalopram and
amitriptyline with QTc prolongation but no associations for other
antidepressants examined including other SSRIs fluoxetine,
paroxetine and sertraline as well as other antidepressants
duloxetine, venlafaxine, buproprion, mirtazapine and nortripty-
line. The New England study included adults ages $18 and the
mean age was 58 (SD=16) years .
In contrast, an observational study of data from the Veterans
Health Administration (VHA) National Registry for Depression
found no increased risk of ventricular arrhythmia or mortality with
citalopram doses of greater than 40 mg/day. 41% of the VHA
cohort was age $60 . No QTc data were presented.
To the best of our knowledge, no other trials have published on
the relationship between citalopram and QT interval in older
adults participating in a placebo-controlled trial. The Citalopram
for agitation in Alzheimer’s Disease (CitAD) trial was designed to
evaluate the efficacy of citalopram for the treatment of clinically
significant agitation in patients with AD. Following the FDA safety
warnings regarding citalopram, CitAD investigators added safety
monitoring for QT prolongation and the objective here is to show
the differences in QT interval for citalopram versus placebo in
older adults with AD.
CitAD QTc Prolongation
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CitAD was an investigator-initiated clinical trial funded by the
National Institute on Aging (NIA) and National Institute of Mental
Health (NIMH) than enrolled participants from August 2009 to
January 2013.CitADis registered
NCT00898807. The study had eight recruiting clinical centers
(seven in the U.S. and one in Canada) and two resource centers
(the chair’s office and the coordinating center). Study participants
were recruited from memory clinics, geriatric psychiatry clinics,
Veterans Administration geriatric clinics, nursing homes, commu-
nity outreach, and Alzheimer Research Centers. CitAD partici-
pants had probable Alzheimer’s disease as defined by NINCDS-
ADRDA  criteria, Mini-Mental State Examination (MMSE)
 scores of 5–28 inclusive, and clinically significant agitation.
The detailed list of eligibility criteria for CitAD has been published
previously . The protocol for CitAD and supporting CON-
SORT checklist are available as supporting information; see
Protocol S1 and Checklist S1.
Participants were randomized using a plan developed by the
coordinating center in a 1:1 ratio to receive citalopram or
matching placebo in parallel. The treatment assignment was given
in form of a medication kit identification code only after eligibility
was confirmed (allocation concealment). A detailed description of
the randomization and concealment methods has been published
. A starting dose of 10 mg was titrated up over 2 weeks to the
target of 30 mg daily, provided as a single dose in the morning of
three capsules each containing 10 mg. Citalopram was purchased
on from commercial wholesale drug suppliers on the open market
and over-encapsulated to facilitate participant and study staff
Participants were followed via in-person study visits at weeks 3,
6, and 9 following enrollment and telephone contacts at weeks 1,
2, 4.5 and 7.5 weeks following enrollment. The data collection
schedule was described in detail previously . Adverse events
were primarily collected via systematic, close-ended questions
regarding known or expected side effects or complications of
citalopram, and through the measurement of electrolyte levels.
Serious adverse events were collected on an individual basis at the
time of the event and when updated information became
The primary results of the CitAD trial have been reported 
and in short, citalopram (at target does of 30 mg/day) improved
agitation, global function, and caregiver burden but was associated
with cognitive worsening and increased anorexia, diarrhea, fever
The study protocol was reviewed and approved by the ethics
committee at each clinical center and the coordinating center:
New York State Psychiatric Institute Institutional Review Board
(Columbia), University Of Pennsylvania Office Of Regulatory
Affairs Institute Institutional Review Board, Centre For Addiction
And Mental Health Research Ethics Board (Toronto), Stanford
University Panel On Human Subjects In Medical Research,
University Of Southern California Keck School Of Medicine
Affairs Institute Institutional Review Board, Medical University of
South Carolina Institute Institutional Review Board For Human
Research, Johns Hopkins Office Of Human Subject Research
Institute Institutional Review Boards, Johns Hopkins Bloomberg
School of Public Health Institutional Review Board, University of
Rochester Research Subjects Review Board.
Figure 1. Participant flow* related to ECG monitoring.
CitAD QTc Prolongation
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Table 1. Baseline characteristics of the patients.
Enrolled after ECG monitoring began*
Age in years, mean (SD)
Women, n (%)
Racial/ethnic group, n (%)
Highest education, n (%)
No High school diploma
High school diploma
Some college/associates degree
Concomitant medications, n (%)
QT interval, mean (SD)
History** of hypertension, n (%)
History** of myocardial infarction, n (%)
Systolic, mean (SD)
Diastolic, mean (SD)
Resting pulse, mean (SD)
*ECG monitoring began on 11Nov2011 following the FDA safety communication regarding citalopram and QT prolongation.**Self or caregiver reported history.
CitAD QTc Prolongation
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Participants provided written consent if they were capable of
providing consent. If the participant is not fully capable of
providing consent, then written consent was obtained from an
authorized legal representative and the participant was asked to
In September 2011, the CitAD Steering Committee (SC)
decided that active subjects should be informed about the FDA
advisory and that participants on 3 study capsules per day
(corresponding to 30 mg daily for those in the citalopram group)
have an ECG as soon as was practical. New dose increases over
20 mg were temporarily halted while the SC waited for the
updated Celexa label to be released.
When the changed label became available shortly after the first
safety communication, there was no change regarding the use of
the medication in individuals over age 60. As a result, the SC
concluded that no change in the dosing scheme was needed but
added an exclusion criterion for individuals with a prolonged
QTc, defined as .450 ms for men and .470 ms for women, as
measured on an ECG conducted at the study’s screening/
enrollment visit using equipment available at the clinical centers;
there was no central calibration of machines or central reading
facility. The cutoffs for prolonged QTc were based on recom-
mendations from an SC-appointed study cardiologist and are
consistent with standard thresholds [4,21]. No other change in the
inclusion or exclusion criteria was deemed necessary. The SC also
added ECG monitoring at the week 3 visit, when the target dose of
30 mg/day was expected to have been reached in most
participants, and also at the first visit after a dose increase to
30 mg for participants on slower titrations. Other ECGs could also
be performed at any time at the discretion of the study physician.
Electrolytes were already being regularly monitored in CitAD, but
magnesium was added to the set of measures. These modifications
were reviewed and approved by the DSMB, funding agency and
by the ethics committee at each center and became effective in
November 2011, after 142 CitAD participants had already been
Following the second revision to the citalopram label in March
2012, the SC reviewed the new label and decided to make no
further changes to the study entry criteria and procedures.
However, the template consent form was revised to state that
the dose of citalopram used in CitAD was higher than the FDA
maximum recommended dose for people over 60.
The CitAD sample size requirements were based on the
primary outcomes and have been published [19,20]. Enrollments
following the introduction of the new ECG monitoring procedures
in 2011 continued to be balanced between the citalopram and
placebo groups. All participants were counted in the group to
which they were assigned regardless of treatment adherence
(‘‘intention-to-treat’’). Baseline characteristics of participants en-
rolled during the entire trial and for those enrolled after ECG
monitoring began are summarized by treatment group using
means and standard deviations for continuous variables and
counts and proportions for categorical variables.
For participants enrolled after November 2011, QTc at week 3
was compared by treatment group using linear regression
controlling for baseline QTc and 95% confidence intervals and
t-tests were calculated. A similar model for change from baseline in
QTc was created and a treatment by enrollment QTc interaction
was included to test for differences in relationship between
enrollment QTc and change in QTc by treatment group. We
defined ‘‘prolonged’’ QTc as QTc.450 ms for men or 470 ms for
women [4,21]. ‘‘Clinically significant increase’’ in the QTc was
defined as an increase $30 ms from enrollment to week 3,
consistent with FDA guidance . The proportion of patients
with prolonged QT and change in QTc$30 ms from enrollment
to week 3 were compared by Fisher’s exact test. These analyses
were not planned at the beginning of the trial because the FDA
advisory and corresponding protocol changes occurred well into
the second half of the trial.
Statistical analyses were performed using SAS version 9.2;
copyright ? 2002–2008 by SAS Institute Inc Cary, NC, USA, and
R version 2.13.1; copyright ? 2011 by the R Foundation for
Figure 2. Baseline and week 3 QTc.
CitAD QTc Prolongation
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Statistical Computing. All p-values are two-sided and p,0.05 was
used as the threshold for statistical significance.
CitAD stopped enrolling participants shortly after the planned
stopping date and enrolled 186 participants in total (94 in
citalopram and 92 in placebo), 48 (24 in citalopram and 24 in
placebo) of which were enrolled after the ECG monitoring began.
The original target enrollment was 200 but was not met due to
slow enrollment at the end of the trial. The flow of participants
with respect to ECG monitoring is shown in Figure 1. Between the
August 2011 FDA advisory and November 2011, 27 patients who
were in active follow-up were monitored informally while protocol
changes were drafted and reviewed by the DSMBs and ethics
committees and subsequently implemented. We did not require
that ECGs performed during this interim period be retrospectively
recorded on data collection forms, although some were captured.
In November 2011 changes were formally implemented, the
patients currently in active follow-up (n=3) and the 48
subsequently enrolled patients had ECG recorded as described
previously. However, one participant was enrolled without an
ECG, one patient refused the week 3 ECG and three patients
missed the week 3 visit.
Baseline characteristics of all participants as well as the subset
that enrolled after new ECG monitoring procedures were
implemented are shown in Table 1. The mean age of all
participants at enrollment was 78 (SD=8). Slightly less than half
(85; 46%) of the participants were women. For more information
on baseline characteristics see Porsteinsson, et al . More than
half (n=111, 60%) of the participants had a history of
hypertension at enrollment and 15 (8%) reported a previous
myocardial infarction. The mean systolic and diastolic blood
pressures were 132 (SD=17) and 73 (SD=11), respectively, with a
mean resting pulse of 68 (SD=10). There were no differences in
the cardiovascular related baseline characteristics between the
treatment groups. The mean baseline QTc interval was 417 mil-
liseconds (ms) (SD=22) and was not different between the two
Forty-four participants had ECGs at both baseline and week 3.
Of these, 31 participants (16 in citalopram, 15 in placebo) were on
3 study capsules per day at the week 3 ECG, 7 (3 in citalopram, 4
in placebo) were on 2 capsules, 4 (2 in citalopram, 2 in placebo)
were on 1 capsule, 1 (in citalopram) was on 0 capsules and 1 (in
placebo) was missing dose information at week 3. The raw QTc
data are shown in Figure 2 and the analysis results are shown in
Table 2. The mean QTc at week 3 was 432 ms (SD=24) in the
citalopram group and 415 ms (SD=25) in the placebo group. The
mean change in QTc from enrollment to week 3 (for all
participants having both measurements regardless of dose) was
14.9 ms (SD=19) in citalopram and 22.9 ms (SD=22) in
placebo. In regression analysis, citalopram was associated with a
longer QTc interval at week 3 compared to placebo; the difference
in week 3 QTc for citalopram compared to placebo adjusting for
enrollment QTc was 18.1 ms (95% CI: 6.1, 30.1; p=0.004) .
The results were unchanged after excluding the one citalopram
participant enrolled after ECG monitoring began that was no
longer taking citalopram at the week 3 ECG.
Almost one third of the participants in the citalopram group
(n=7, 32%) had a clinically significant increase of greater than
30 ms from enrollment to week 3 compared to only 1 (5%) in the
placebo group (Fisher’s exact p=0.046) . Of the patients with
any follow-up ECGs (n=50), only four patients met the gender-
specific threshold for prolonged QTc at any point during follow-
Table 2. ECG monitoring.
Number of participants enrolled after ECG monitoring began
Number of participants with at least one follow-up ECG
At least one prolonged QT interval during follow-up*, n (%)
Number of participants with enrollment and week 3 ECG
Mean (SD) QT interval at week 3
Mean (SD) change in QT interval from enrollment to week 3
Difference in QT interval (Cit - Plb) at week 3**
(95% CI: 6.1, 30.1)
Increase in QT interval $30 ms*, n (%)
*P-value calculated using Fisher’s exact test.**P-value calculated using linear regression of week 3 QT interval on treatment group controlling for baseline QT interval. Positive difference indicates longer QTc interval in citalopram.
CitAD QTc Prolongation
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Figure 3. Change in QTc by baseline QTc and treatment group.
Figure 4. ECG of patient with prolonged QTc and bigeminy.
CitAD QTc Prolongation
PLOS ONE | www.plosone.org7 June 2014 | Volume 9 | Issue 6 | e98426
up (3 [13%] in citalopram versus 1 [4%] in placebo, Fisher’s exact
p=0.611) . Although the number of participants on a dose
lower than 3 caps per day was small, it is notable that 2 of the 3
citalopram participants on 20 mg/day and 1 of the 2 citalopram
participants on 10 mg/day had an increase $30 ms from baseline
to 3 weeks.
Changes in QTc by baseline QTc and treatment assignment are
shown in Figure 3. The change in QTc was inversely related to the
enrollment QTc (combined [citalopram and placebo] slope
estimate=20.293 [95% CI: 20.593, 20.007], p=0.055) sug-
gesting higher enrollment QTc was associated with lower change
in QTc, possibly due to regression to the mean but also influenced
by the placebo outlier (see Figure 3, top right corner of figure).
However, the relationship between enrollment QTc and change in
QTc did not differ statistically between treatment groups
(interaction p=0.372), indicating that the difference in change
in QTc between treatment groups was fairly constant across
varying values of enrollment QTc. Results with the aforemen-
tioned influential point removed are available in the Text S1 and
One of the men in the citalopram group that displayed
prolonged QTc at week 3 (492 ms) also showed bigeminy on the
ECG. The ECG is shown in Figure 4. This participant had a
baseline QTc of 444 ms and was also taking alfuzosin which is
known to lengthen QT (QTdrugs.org). The study cardiologist
(masked to treatment group) recommended stopping study drug
after the week 3 ECG and the patient continued follow-up off of
drug without any complications but no follow-up ECGs are
Two participants in the citalopram group had serious adverse
events labeled as ‘syncope’ that required hospitalization. The
syncope events occurred before ECG monitoring began so no
QTc data are available. No syncope events were reported in the
placebo group; however, one patient in the placebo group fell and
broke her hip while reaching for belongings on a dresser. More
information about serious adverse events is available in the
primary report of CitAD . No participants in either group had
a cardiovascular related death or other cardiovascular related
serious adverse events. The single reported death, in the placebo
group, was from a previously undetected lung cancer.
The mean QTc for CitAD participants at enrollment was
similar to that seen in other studies of older adults [23–26].
Compared with placebo, the increase in QTc interval for
citalopram was approximately 18 ms longer and the difference
between the groups was independent of the baseline QTc value.
This increase is higher than what we would expect based on the
data in the FDA drug safety communication  but older
patients have diminished clearance of citalopram; in a pharma-
cokinetic analysis of 106 subjects (ages 22–93), investigators found
that citalopram clearance decreased 0.23 L/h for every year of
Although the study was not designed to examine differences in
QTc, the blocked randomization scheme produced comparable
groups after the ECG monitoring procedures were added. In the
placebo group, the difference between the baseline and week 3
QTc intervals were centered close to zero (at 23 ms) indicating
fairly stable measurements on average, although one participant
had a large change in QTc in the placebo group. Any noise added
because of inherent variability in ECG reads or in differing QT to
QTc conversions, or because the ECGs were done at different
times of the day [4,5] should be equally distributed in the
citalopram and placebo groups, and in fact, variance estimates
were similar in the two groups. The lack of standardization of QTc
calculation could affect the classification of ‘prolonged QT’
although the mean resting heart rate in the CitAD participants
was 68 (SD=10) and the various formulae give similar conversions
in this range . This lack of precision in estimating QTc also
reflects the reality of using this equipment and is important for
generalization to clinical practice.
QT prolongation is a surrogate measure for arrhythmia .
Many drugs are known to cause QT prolongation and the degree
of QT prolongation caused by citalopram in the current study was
comparable with increases in QTc due to other drugs known to
interfere with myocardial repolarization [28,29]. FDA guidance
for industry states that drugs that are associated with mean
increases of .20 ms ‘‘have a substantially increased likelihood of
being proarrhythmic’’  and our observed difference is
approaching that magnitude of increase. Whether citalopram
was directly responsible for any adverse clinical outcomes in our
cohort is unclear. A study with a larger sample size would be
needed to determine if these changes in QTc were indicative of
changes in incidence of arrhythmia and cardiac events. Even in
this small sample, two patients in the citalopram group had
unexplained syncope (prior to the onset of ECG monitoring) and
one citalopram patient experienced profound QTc prolongation
and bigeminy (frequently a harbinger of impending TdP),
suggesting the possibility of a real and worrisome citalopram-
induced effect. The latter patient was also taking alfuzosin, a drug
that should be used with caution in patients who are taking other
medications that prolong the QT interval, such as citalopram .
We did not allow enrollment of men with QTc.450 or women
with QTc.470 after the FDA advisory so it is possible that we are
underestimating the proportion of older adults who might develop
prolonged QTc after initiating citalopram.
Our results provide data to support the FDA warning against
the use of citalopram in doses higher than 20 mg/day in people
over 60. Citalopram, at 30 mg/day, was associated with
improvement in agitation in patients with AD but also with
concerning cognitive effects and QT prolongation.
Resource center representatives:
ment group excluding influential point.
Change in QTc by baseline QTc and treat-
Sensitivity analyses supporting information.
Access to study protocol and data
The CitAD protocol is available on the study website: https://www.
CitAD datasets are available upon request. All requests must be vetted
by the Steering Committe and must include an analysis plan. If the request
is approved, the requestor must have IRB approval to receive data.
Requests can be submitted to the address provided on the study website.
The members of the CitAD Research Group are:
Steering Committee voting members (responsibilities: study
design and conduct)
Resource center representatives:
CitAD QTc Prolongation
PLOS ONE | www.plosone.org8 June 2014 | Volume 9 | Issue 6 | e98426
Constantine Lyketsos, MD, MHS (chair)
Dave Shade, JD (vice chair)
Clinical center directors:
D.P. Devanand, MD
Jacobo Mintzer, MD, MBA
Paul Rosenberg, MD
Bruce G. Pollock, MD, PhD
Anton Porsteinsson, MD
Lon S. Schneider, MD
Jerome Yesavage, MD
Daniel Weintraub, MD
Resource centers (responsibility: study administration)
Chair’s Office, Johns Hopkins Bayview and Johns Hopkins School of Medicine,
Constantine Lyketsos, MD, MHS (chair)
Allison Carlson (lead coordinator)
Dimitri Avramopoulos, MD, PhD (study geneticist)
Cynthia Munro, PhD (study neuropsychologist)
Peter Rabins, MD, MPH (conflict of interest officer)
Coordinating Center, Johns Hopkins Bloomberg School of Public Health, Baltimore:
Dave Shade, JD (director)
Anne Shanklin Casper, MA, CCRP (lead coordinator)
Lea Drye, PhD
Constantine Frangakis, PhD
Curtis Meinert, PhD
Susan Tonascia, ScM
Ozlem Topaloglu, PhD
Vijay Vaidya, MSc, MPH
Project Office, National Institute on Aging, Bethesda:
Laurie Ryan, PhD (project officer)
Clinical centers (responsibility: data collection)
Johns Hopkins Bayview and Johns Hopkins School of Medicine, Baltimore:
Paul Rosenberg, MD (director)
Julia Pedroso, RN, MA (lead coordinator)
Alyssa Bergey, MA
Carol Gogel, RN
Christopher Marano, MD
Jamie Pollutra, RN
Lynn Smith, MA
Martin Steinberg, MD
Columbia University Medical Center, Columbia:
D.P. Devanand, MD (director)
Corazon de la Pena (lead coordinator)
Gregory H. Pelton, MD
Medical University of South Carolina, Charleston:
Jacobo Mintzer, MD, MBA (director)
Nicholas Gregory (lead coordinator)
Olga Brawman-Mintzer, MD
Marilyn Stuckey, RN
Markeeta Hatchell, RN
University of Pennsylvania School of Medicine, Philadelphia:
Daniel Weintraub, MD (director)
Jamie Czerniakowski (lead coordinator)
Suzanne DiFilippo, RN
Joel Streim, MD
University of Rochester School of Medicine, Rochester:
Anton Porsteinsson, MD (director)
Bonnie Goldstein, MS, NP (coordinator)
Susan Salem-Spencer, RN, MSN (coordinator)
Nancy Kowalski, MS, RNC
Kimberly S. Martin, RN
Jeanne LaFountain, RN
Stanford University School of Medicine
Jerome Yesavage, MD (director)
Jeff Newell (lead coordinator)
Wes Ashford, MD
Karen Bratcher, RN
Steven Chao, MD
Jennifer Kaci Fairchild, PhD
Leah Friedman, PhD
Gerald Georgette, RN
Vyjeyanthi Periyakoil, MD
Arthur Traum, MD
Alda Vicencio, RN
University of Toronto
Bruce G. Pollock, MD, PhD, FRCPC (director)
Dielle Miranda (lead coordinator)
Robert Bies, PhD
Amer Burhan, MD
Phil Gerretsen, MD
Zahinoor Ismail, MD
Benoit H. Mulsant, MD, MS
Minh-Quan Nguyen, HBsc
Tarek Rajji, MD
David Tang-Wai, MD
University of Southern California Keck School of Medicine
Lon S. Schneider, MD (director)
Maurcio Becerra (lead coordinator)
Karen Dagerman, MS
Sonia Pawluczyk, MD
Bryan Spann, DO, PhD
Liberty Teodoro, RN
Data Safety and Monitoring Board members (responsibility: review
of accumulating data on safety and efficacy)
Kristine Yaffe, MD (chair)
Stephan Arndt, PhD
Jeffrey Cummings, MD
Lea Drye, PhD
Constantine Lyketsos, MD
Laurie Ryan, MD
Dave Shade, JD
Conceived and designed the experiments: LD DD CF CLM JM CM BP
AP PVR PBR LS DMS DW JY CL. Performed the experiments: LD DD
CM CLM JM GP BP AP PBR LS DMS DW JY CL. Analyzed the data:
LD CF DS. Wrote the paper: LD DS. Critical review and editing of
manuscript: DD CM CLM JM BP AP PVR PBR LS DMS DW JY CL.
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