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1552
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The Annals of Pharmacotherapy
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2001 December, Volume 35
C ASE REPORTS
www.theannals.com
C
italopram is a substituted bicyclic phthalane derivative
that is the most selective of the available selective sero-
tonin-reuptake inhibitors (SSRIs).
1
It was first released in
Europe in 1989 and in Australia in 1998. Large, random-
ized controlled trials of its use in depression compared
with tricyclic antidepressants and other SSRIs suggest that
citalopram has fewer adverse effects and is well tolerat-
ed.
2,3
There has been concern regarding the toxicity of citalo-
pram, mainly in overdose.
4,5
Large overdoses of citalopram
(>600 mg) can result in seizures, QT lengthening, and oth-
er electrocardiographic (ECG) abnormalities.
6-8
There is
presently little evidence to indicate that citalopram causes
ECG abnormalities at therapeutic doses, with two stud-
ies
9,10
demonstrating no significant effects on QRS and
QTc intervals. However, like other SSRIs, citalopram can
cause a small but significant decrease in heart rate com-
pared with placebo.
9
Bradycardia (HR <60 beats/min) appears to be an un-
common but potentially important adverse drug reaction to
citalopram. Premarketing information is difficult to access,
but the Food and Drug Administration–approved product
information
11
for Celexa (citalopram) lists bradycardia as
an infrequent adverse event. Infrequent adverse events are
defined as those occurring in less than 1/100 patients but in
at least 1/1000 patients. One small study
12
demonstrated
that therapeutic use of citalopram and fluoxetine induced
bradycardia more often than amitriptyline. Another trial
13
reported bradycardia in two of 21 patients on citalopram,
with one patient developing a heart rate of 44 beats/min.
Postmarketing surveillance
9
of citalopram in more than 5
million people revealed only 17 reports of prolonged QTc
interval and/or arrhythmia; however, the number of cases
of bradycardia was not given. There has been one pub-
lished report
14
of asymptomatic bradycardia in a patient re-
Citalopram-Induced Bradycardia and Presyncope
Geoffrey K Isbister, Felicity H Prior, and Aidan Foy
OBJECTIVE: To report a case of symptomatic bradycardia and hypotension that resulted from the therapeutic use of citalopram and
to review any previous reports in the literature, from the manufacturer, and the Australian Drug Reaction Advisory Committee
(ADRAC).
CASE SUMMARY: A 60-year-old white woman who had been taking citalopram 20 mg/d for two weeks presented to the hospital with
a heart rate of 39 beats/min, mild hypotension (systolic BP 105 mm Hg), and a normal electrocardiogram (QTc <440 msec),
following a presyncopal episode. The patient was admitted for cardiac monitoring, and citalopram was discontinued. The
bradycardia and hypotension resolved in the 48-hour period following cessation of citalopram. No other medical or pharmacologic
cause was found for the adverse drug reaction.
DISCUSSION: Bradycardia has been reported rarely with citalopram in therapeutic doses, but this is the first detailed case with a dose
of only 20 mg. The manufacturer reports bradycardia as an infrequent adverse effect (0.1–1%) of citalopram. There have been no
reports to ADRAC or to the manufacturer in postmarketing surveillance. There is a case report of asymptomatic bradycardia in a
patient whose dose was increased to 40 mg. In the case reported here, there was no QTc prolongation consistent with previous
reports. The sinus bradycardia reported more often with therapeutic doses would appear to be distinct to QT abnormalities seen
with citalopram overdose.
CONCLUSIONS: Citalopram should be used with care in the elderly and in persons with a history of heart disease. Heart rate and
blood pressure should be monitored in the first week of therapy and when doses are modified.
KEY WORDS: bradycardia, citalopram.
Ann Pharmacother 2001;35:1552-5.
Author information provided at the end of the text.
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ceiving citalopram 40 mg/d and a report
15
of a citalopram
overdose causing sinus bradycardia and hypotension re-
quiring a temporary pacemaker for six days.
We report a case of symptomatic bradycardia in a patient
who had been taking citalopram 20 mg/d. We also contact-
ed the Australian Drug Reaction Advisory Committee
(ADRAC) to see whether there were any other sponta-
neous reports of bradycardia associated with citalopram.
CASE REPORT
A 60-year-old white woman presented to the emergency depart-
ment (ED) on December 10, 2000, with lumbar back pain fol-
lowing an episode of presyncope. The patient had leaned over,
coughed, then felt unwell and faint, and developed back pain.
She continued to be “shaky” and felt she was “going to die”; she
presented to the hospital several hours later. She continued to
have “funny feelings” in her stomach, but the back pain was re-
solving. Her past medical history included depression and anxi-
ety, gastro-esophageal reflux, recurrent urinary tract infections,
and an appendectomy. She was a smoker, denied alcohol use, and
reported no allergies. Her medications included omeprazole 20
mg/d, alprazolam 1 mg as required for anxiety, and citalopram 20
mg/d for two weeks. There was no recent history of feeling un-
well.
On examination, the patient was alert, with HR 50 beats/min,
BP 105/57 mm Hg, RR 20 breaths/min, and T 37.1 ˚C. On car-
diovascular examination, she had dual heart sounds, no murmurs
or additional sounds, normal jugular venous pressure, and normal
peripheral pulses. Chest and abdominal examinations were nor-
mal. Her neurologic examination was also normal. On examina-
tion of the woman’s back, there was mild right lumbosacral para-
vertebral tenderness and pain on movement. Her HR varied from
39 to 50 beats/min on cardiac monitoring, and a 12-lead ECG
showed sinus bradycardia (39 beats/min), QT 460 msec, and QTc
370 msec. The HR increased to 72 beats/min after she stood up
to walk. Records of previous admissions to the ED revealed HRs
ranging from 60 to 70 beats/min, and BP 125/70 mm Hg, which
was confirmed by her usual physician.
A suspected diagnosis of bradycardia causing presyncope sec-
ondary to citalopram was made. The back pain was thought to be
muscular strain following bending over and straightening sud-
denly. Citalopram was discontinued, and the woman was admit-
ted to the medical unit overnight for hourly HR and BP measure-
ments (Figure 1). The following morning, she reported fatigue
and nausea. Vital signs showed HR 50 beats/min and BP 95/50
mm Hg. She was then discharged home.
Forty-eight hours after her initial presentation, the woman was
seen by her local physician. She was well, with HR 66 beats/min
and BP 120/70 mm Hg. Holter monitoring showed no significant
abnormalities. She had no further problems. The depression was
subsequently treated with another antidepressant with no adverse
effects.
Discussion
The case we present describes an elderly woman who
developed symptomatic sinus bradycardia and mild hy-
potension two weeks after commencing treatment with
citalopram 20 mg/d. She had at least one presyncopal
episode, which resulted in a muscular injury, but no further
complications. The cardiovascular effects resolved in 48
hours following cessation of citalopram.
According to the Naranjo probability scale,
16
this reac-
tion was probable. No other drugs had been recently initi-
ated and thus implicated. There was no other medical rea-
son to explain the episode of bradycardia. The woman usu-
ally had a slow heart rate, but not <60 beats/min. The use
of omeprazole, a CYP2C19 inhibitor, may have caused in-
creased concentrations of citalopram, which is a substrate
of CYP2C19. The patient was not rechallenged because of
the considerable risk of recurrent bradycardia.
Although symptomatic bradycardia can be a serious
problem, it appears to be an infrequent adverse effect of
citalopram. The incidence of bradycardia in premarketing
clinical trials was between 0.1% and 1%.
11
There have
been two detailed reports
13,14
of bradycardia with therapeu-
tic doses of citalopram, and a recent report
15
of severe pro-
tracted bradycardia and symptomatic hypotension follow-
ing an overdose of citalopram 800 mg. This patient re-
quired a temporary pacemaker for six days, but recovered
without sequelae.
15
There have been no reports of brady-
cardia with citalopram to ADRAC, the national body in
Australia that collects data on adverse reactions; however,
these are all spontaneous reports. This type of postmarket-
ing data, like the postmarketing surveillance of the compa-
ny,
1
is likely to underestimate the true incidence of adverse
effects.
17
This may be particularly true for bradycardia,
which can be asymptomatic in many patients.
As of March 2001, ADRAC had 18 reports of heart rate
and rhythm disorders with citalopram implicated as the
suspected agent. Tachycardia and palpitations were the
most common adverse effects described and, in the majori-
ty of cases, these were also associated with other symp-
The Annals of Pharmacotherapy
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2001 December, Volume 35
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1553
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Figure 1. Time course of heart rate and blood pressure in the 48 hours fol-
lowing presentation, time zero being when the patient presented to the emer-
gency department. ▲ = systolic; ▼ = diastolic.
toms of serotonin excess (increased sweating, agitation, di-
arrhea, tremor).
18
There were eight reports of palpitations,
with causality assessed as certain in three cases, probable
in three cases, and possible in two cases. Six cases of
tachycardia were reported, with causality assessed as prob-
able in five cases and possible in one case. The remaining
four cases were assessed as only possible and included re-
ports of ventricular ectopic beats, supraventricular tachy-
cardia, prolonged QT interval, and cardiac arrest.
In the case we describe, the patient’s ECG demonstrated
only sinus bradycardia, with no evidence to suggest any
other abnormalities. Although the QT length was 460
msec, the QTc was much shorter at 370 msec, which is
within the normal range.
19
In the only other detailed re-
port
14
of bradycardia, the QTc was 463 msec while the pa-
tient received citalopram 40 mg, and 440 msec after the
drug was ceased. This is only a borderline increase in the
QTc for women (>470 msec regarded as significant), and
the small decrease after citalopram was discontinued sug-
gests there was a preexisting abnormality.
19
QT abnormalities have been reported with citalopram
overdoses. In a case series from Sweden,
8
six of 18 pa-
tients who ingested more than 600 mg of citalopram had
QT abnormalities. Conversely, in another reported
15
over-
dose causing severe bradycardia, there was no change in
the QTc interval. The QT prolongation seen with citalo-
pram overdose would appear to be distinct to the sinus
bradycardia that has been reported more often with thera-
peutic doses.
12-14
In clinical trials, the most common adverse effects asso-
ciated with citalopram were nausea, dry mouth, somno-
lence, and, in elderly patients, increased sweating.
1
The pa-
tient reported here had nausea and significant symptoms
that resulted from the bradycardia and presyncope, but no
increased sweating or somnolence.
Citalopram, like other SSRIs, is more commonly report-
ed
8
to cause tachycardia in both therapeutic doses and in
overdose. This is supported by reports to ADRAC, where
the majority of rhythm disorders were either palpitations or
tachycardia. Nine of the 12 cases reported to ADRAC de-
scribed associated symptoms of serotonin toxicity. Al-
though there have been only a few reports
20,21
of citalopram
alone causing serotonin syndrome, it is likely that, in many
cases, citalopram-induced tachycardia is associated with
other evidence of serotonin toxicity.
Summary
We report a case of symptomatic bradycardia and hy-
potension that was probably caused by citalopram. Al-
though this is a potentially serious adverse effect, it appears
to be infrequent, based on our own research and previous
large studies.
1,9
We support the current recommendations
in the company’s product information
22
that citalopram
should be used with care in elderly patients and in persons
with known heart disease. The patient’s heart rate and
blood pressure should be monitored during the first week
of citalopram use, and when changes to the dose are made.
Geoffrey K Isbister BSc MB BS, Senior Registrar, Department of
Clinical Toxicology and Pharmacology, Newcastle Mater Hospital,
Newcastle, Australia
Felicity H Prior BPharm Grad Dip Epi (Pharmaco), Director, Hunter
Drug Information Service, Newcastle Mater Hospital
Aidan Foy FRACP MD, Director and Associate Professor, Depart-
ment of Medicine, Newcastle Mater Hospital
Reprints: Geoffrey K Isbister BSc MB BS, Department of Clinical
Toxicology and Pharmacology, Newcastle Mater Misericordiae Hos-
pital, Locked Bag 7, Hunter Region Mail Centre NSW 2310, New-
castle, Australia, FAX 612 49 211 870, E-mail gsbite@bigpond.com
We thank ADRAC for supplying the information on adverse drug reactions to citalo-
pram in Australia. We also thank Ian Whyte MBBS FRACP for his advice.
References
1. Willetts J, Lippa A, Beer B. Clinical development of citalopram. J Clin
Psychopharmacol 1999;19(5 suppl 1):36S- 46S.
2. Ekselius L, von Knorring L, Eberhard G. A double-blind multicenter tri-
al comparing sertraline and citalopram in patients with major depression
treated in general practice. Int Clin Psychopharmacol 1997;12:323-31.
3. Bech P, Cialdella P. Citalopram in depression — meta-analysis of intend-
ed and unintended effects. Int Clin Psychopharmacol 1992;6(suppl 5):
45-54.
4. Ostrom M, Eriksson A, Thorson J, Spigset O. Fatal overdose with citalo-
pram. Lancet 1996;348:339- 40.
5. Power A. Drug treatment of depression. Citalopram in overdose may re-
sult in serious morbidity and death. BMJ 1998;316:307-8.
6. Personne M, Persson H, Sjöberg G. Citalopram toxicity. Lancet 1997;
350:518-9.
7. Barbey JT, Roose SP. SSRI safety in overdose. J Clin Psychiatry
1998;59(suppl 15):42-8.
8. Personne M, Sjöberg G, Persson H. Citalopram overdose — review of
cases treated in Swedish hospitals. J Toxicol Clin Toxicol 1997;35:237-
40.
9. Rasmussen SL, Overo KF, Tanghoj P. Cardiac safety of citalopram:
prospective trials and retrospective analyses. J Clin Psychopharmacol
1999;19:407-15.
10. Pedersen OL, Kragh-Sorensen P, Bjerre M, Overo KF, Gram LF. Citalo-
pram, a selective serotonin reuptake inhibitor: clinical antidepressive and
long-term effect — a phase II study. Psychopharmacology (Berl) 1982;
77:199-204.
11. Product information. Celexa TM (citalopram). Forest Pharmaceuticals,
USA. http://www.fda.gov/cder/foi/nda/98/020822a_appltr_prntlbl.pdf
[cited 2001 October 26].
12. Hosak L, Tuma I, Hanus H. A comparative study of three antidepres-
sants with different mechanisms of action in hospitalized patients. Ceska
Slovenska Psychiatrie 1999;95:146-56.
13. Dufour H, Bouchacourt M, Thermoz P, Viala A, Phak RP, Gouezo F, et
al. Citalopram — a highly selective 5-HT uptake inhibitor — in the treat-
ment of depressed patients. Int Clin Psychopharmacol 1987;2:225-37.
14. Favre MP, Sztajzel J, Bertschy G. Bradycardia during citalopram treat-
ment: a case report. Pharmacol Res 1999;39:149-50.
15. Rothenhausler H-B, Haberl C, Ehrentraut S, Kapfhammer H-P, Weber
MM. Suicide attempt by pure citalopram overdose causing long-lasting
severe sinus bradycardia, hypotension and syncopes: successful therapy
with a temporary pacemaker. Pharmacopsychiatry 2000;33:150-2.
16. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al.
A method for estimating the probability of adverse drug reactions. Clin
Pharmacol Ther 1981;30:239- 45.
17. Kennedy DL, Goldman SA, Lillie RB. Spontaneous reporting in the
United States. In: Strom BL, ed. Pharmacoepidemiology. 3rd ed. Chi-
chester, UK: John Wiley & Sons, 2000:151-74.
18. Lane R, Baldwin D. Selective serotonin reuptake inhibitor–induced sero-
tonin syndrome: review. J Clin Psychopharmacol 1997;17:208-21.
19. Moss AJ. The QT interval and torsade de pointes. Drug Saf 1999;21
(suppl 1):5-10.
20. Fischer P. Serotonin syndrome in the elderly after antidepressive
monotherapy. J Clin Psychopharmacol 1995;15:440-2.
21. Voirol P, Hodel PF, Zullino D, Baumann P. Serotonin syndrome after
small doses of citalopram or sertraline. J Clin Psychopharmacol 2000;
20:713- 4.
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GK Isbister et al.
Case Reports
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22. Product information. Cipramil TM (citalopram). Lundbeck, Australia Pty.
1998. In: 2001 MIMS annual. 25th ed. Singapore: Tien Wah Press (Pte.),
2001.
EXTRACTO
OBJETIVO: Reportar un caso de bradicardia sintomática e hipotensión que
resultó del uso terapéutico de citalopram. Repasar los informes previos
en la literatura, del fabricante y del Comité Asesor de Reacciones de
Fármacos Australiano (ADRAC, por sus siglas en inglés).
RESUMEN DEL CASO: Una paciente femenina de 60 años de edad que
había estado tomando 20 mg de citalopram diarios por dos semanas se
presentó al hospital con una frecuencia cardíaca (HR) de 39 bpm,
hipotensión leve (presión sistólica <100 mg Hg) y un ECG normal (QTc
<440 msec) después de un episodio de pre-síncope. La paciente fue
admitida para seguimiento cardíaco, y el citalopram fue descontinuado.
La bradicardia y la hipotensión se resolvieron en un periodo de tiempo
de 48 horas después de la suspensión del citalopram. No se encontró
ninguna otra causa médica o farmacológica para la reacción adversa al
fármaco.
DISCUSIÓN: La bradicardia raramente ha sido reportada con el uso de
citalopram en dosis terapéuticas, pero este es el primer caso detallado
con una dosis de sólo 20 mg. El fabricante reporta la bradicardia como
un efecto adverso no frecuente (0.1–1.0%). No han habido reportes a la
ADRAC o al fabricant en las evaluaciones post-mercadeo. Existe un
informe de un caso de bradicardia sintomática en un paciente a quien se
le aumentó la dosis a 40 mg. En el caso reportado al presente, no hubo
prolongació de QTc consistente con informes previos. La bradicardia
sinusal reportada más frecuentemente con dosis terapéuticas parecería
distinta a las anormalidades de QT observadas con una sobredosis de
citalopram.
CONCLUSIONES: Citalopram debe usarse con cuidado en ancianos y en
personas con un historial de enfermedad cardíaca. El ritmo cardíaco y la
presión sanguínea deben ser monitoreadas durante la primera semana.
Brenda R Morand
RÉSUMÉ
OBJECTIF: Signaler un cas d’hypotension et de bradycardie
symptomatique résultant de l’utilisation de citalopram. Réviser tout cas
signalé antérieurement dans la documentation scientifique, au
manufacturier et à l’Australian Drug Reaction Advisory Committee
(ADRAC).
PRÉSENTATION SOMMAIRE DU CAS: Une dame âgée de 60 ans qui prend 20
mg de citalopram par jour depuis deux semaines se présente à l’hôpital
avec un rythme cardiaque de 39 battements par minute, une hypotension
légère (tension artérielle systolique <100 mm Hg) et un électrocardio-
gramme normal (QTc <440 msec) après avoir failli s’évanouir. La
patiente a été admise pour un monitorage cardiaque, et le citalopram a
été cessé. La bradycardie et l’hypotension se sont résorbées dans les 48
heures suivant l’arrêt du citalopram. Aucune autre cause médicale ou
pharmacologique n’a été trouvée pour expliquer cet effet indésirable.
DISCUSSION: La bradycardie a été signalée rarement avec le citalopram
utilisé à dose thérapeutique, mais il s’agit du premier cas décrit avec une
dose de seulement 20 mg. Le manufacturier présente la bradycardie
comme étant un effet indésirable peu fréquent (0.1% à 1%) du
citalopram. Aucun cas n’a été signalé à l’ADRAC ou au manufacturier
depuis la mise en marché du produit. On a retrouvé un cas de
bradycardie asymptomatique signalé chez un patient dont la dose venait
d’être augmenté à 40 mg. Dans le cas décrit ici, comme dans les cas
précédemment signalés, il n’y a pas eu de prolongation du QTc. La
bradycardie sinusale signalée plus souvent avec des doses
thérapeutiques semblerait distincte des anormalités du QT rencontrées
lors d’une surdose de citalopram.
CONCLUSIONS: Le citalopram devrait être utilisé avec précaution chez les
personnes âgées et chez celles avec un antécédent de maladie cardiaque.
Le rythme cardiaque et la pression sanguine devraient être surveillés
durant la première semaine de traitement.
Marie Larouche
