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QTc prolongation and torsades de pointes associated with
combination therapy of fluoxetine and amiodarone: a case
report and literature review
Anhua Wei1, Zhichun Gu2, Xiaoyan Liu2
1Department
of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong
University of Science and Technology, Wuhan 430030, China;
2Department
of Pharmacy, RenJi Hospital, School of Medicine, Shanghai Jiao Tong
University, Shanghai 200127, China;
Abstract:
Objective: To emphasize the importance of considering drug-drug interactions to
minimize the accidence of the serious, potentially life-threatening ventricular
tachyarrhythmia.
Case summary: A 62-year-old man diagnosed with dilated cardiomyopathy was
admitted to the implanted cardioverter-defibrillator (ICD). The initial value of
pacing rhythm was programmed to 60 bpm and the QTc interval on admission was
normal. After given fluoxetine for the comorbidity of depression, the QTc interval
gradually increased. On the third day, when intravenous and orally amiodarone were
administrated, the continuous ECG monitoring showed a prolonged QTc interval, an
R on T phenomenon and twisting of the QRS axis around the isoelectric line, which
was refined as an episode of TdP.
Conclusion: This is the first report on QTc prolongation and Tdp associated with
combination therapy of fluoxetine and amiodarone, which illustrates the importance
of considering drug-drug interactions. Clinicians should be cautious about cardiac
effects when using an SSRI, especially in combination therapy with other
medications that are known to prolong the QTc interval.
Keywords: Fluoxetine; Amiodarone; QTc; Tdp;
Introduction
Prolongation of the corrected QT interval (QTc) is present in 1 of every 5000
people and may lead to serious, potentially life-threatening, ventricular
tachyarrhythmia, such as torsades de pointes (Tdp). Many drugs, including
antidepressants, were reported to induce the QTc prolongation. Compared with
tricyclic antidepressants (TCAs), use of selective serotonin reuptake inhibitors
(SSRIs) such as fluoxetine was less likely to cause severe cardiac adverse effects.
Here, we present one case of Tdp after the concurrent administration off fluoxetine
and amiodarone, and review the cardiac effects of SSRIs.
Case report
A 62-year-old man with past medical history of asthma presented to the
cardiovascular department with shortness of breath, chest tightness, fever,
orthopnea, cough and expectoration for the past a week. Vital signs were normal:
blood pressure 137/88 mmHg and heart rate 98 bpm. Her physical examination
showed barrel chest and dry rale spread in both lungs. Serum potassium,
magnesium, liver function and renal function tests were within normal limits except
for serum BNP (1320pg/ml). Echocardiography showed depressed left ventricular
function with left ventricular ejection fraction of 32%. Hence, the diagnosis of
dilated cardiomyopathy was confirmed and the implanted cardioverter-defibrillator
(ICD) (MAXIMO II VR D284VRC, Medtronic,America) was placed. The initial value of
pacing rhythm was programmed to 60 bpm. The electrocardiogram (ECG) on
admission demonstrated a QTc interval of 386 ms (Fig. 1A). Fluoxetine was given to
this patient for the co morbidity of depression. During the next 3 days, the QTc
interval gradually increased to 501ms and the ventricular rate was 91 bpm (Fig. 1B).
On the third day, the patient frequently experienced episodes of ventricular
premature beat. Intravenous amiodarone was given as a 450 mg bolus followed by
600 mg orally daily to stabilize the electrical activity of the heart. The continuous
ECG monitoring showed a prolonged QTc interval, an R on T phenomenon and
twisting of the QRS axis around the isoelectric line, which was refined as an episode
of torsades de pointes (TdP) (Fig. 1C). After 16 seconds, conversion to sinus rhythm
was achieved automatically, and the relapse of Tdp was recorded again after 12h (Fig.
1D). The patient was treated with magnesium and potassium and the ICD–brady
pacing mode was reprogrammed to 90 bpm for overdriving (Fig. 1E). Meanwhile,
both of fluoxetine and amiodarone were discontinued. These maneuver prevented
further episodes of Tdp. ECG taken next day showed pacing rhythm of 89 bpm with
QTc interval of 493ms. During the next 2 days, the QTc interval gradually decreased
without clinically significant arrhythmias. Thus, VVI pacing was programmed to the
initial value of 60 bpm. After a few days, ECG showed the QTc interval of 446ms and
the patient was discharged home without any complications (Fig. 1F).
Discussion
This is the first report on QTc prolongation and Tdp associated with
combination therapy of fluoxetine and amiodarone. Meanwhile, amiodarone may
raise the concentration of fluoxetine by cytochrome P450 (CYP) 2D6 enzymes based
drug-drug interaction.
Firstly, we found a clear temporal relationship between QTc prolongation and
the use of fluoxetine in this case. Fluoxetine is a member of the drug family known as
selective
serotonin
reuptake
inhibitors
(SSRIs).
Compared
with
tricyclic
antidepressants (TCAs), SSRIs have shown significant antidepressant activity and
good tolerability [1]. When taken alone, fluoxetine was associated with a low risk of
QTc prolongation and Tdp [2]. Roose SP et al. [3] reported that fluoxetine given at the
normal dose had a minimal effect on QTc interval compared with placebo. However,
overdose or interaction with other medications known to cause QTc prolongation
could increase the likelihood of cardiac toxicity with bradycardia, QTc prolongation,
and Tdp [4]. We searched the PubMed database for studies containing the keywords
“fluoxetine,” “torsades de pointes” and “QTc” and obtained 5 case reports, describing
in Table 1[5-9]. In these cases, combining with other QTc interval–prolonging
medications was considered as the major cause of Tdp, and the electrolyte
disturbancies, substance abuse and cardiac history were likely additional risk
factors. Rajamani Set al.
[10]
reported that the possible mechanisms were the
concentration-dependent and selective blockade of the human ether-a-go-go–
related gene (hERG) via direct channel blocking and indirectly disrupting channel
protein trafficking. In our case, compared with day 1 in hospital (QTc=386ms), QTc
interval was gradually prolonged to 501ms on days 3. The QTc prolongation was
exceptional with the effect of fluoxetine.
A QTc of over 500ms is associated with a 2 to 3 fold increase in Tdp risk. Many
other risk factors may increase a patient’s risk for Tdp development, including
female sex, age over 65 years, bradycardia, hypokalemia, hypomagnesaemia,
underlying heart disease, renal and hepatic dysfunction, higher concentrations of
one more QTc-prolonging drugs and genetic predisposition
[11].
In this case, the
patient was 62-year-old man with the dilated cardiomyopathy. The main laboratory
tests on admission were normal and a QTc interval was 386 ms. On the third day,
amiodarone was given to stablize the electrical activity of heart. Amiodarone is
known to be a class III antiarrhythmic drug with the QTc prolongation potential. The
mechanism is also blockade of hERG encoded Ikr
[12].
Drugs that block the Ikr
channel increase the QTc interval and allow inward current, particularly calcium, to
reactivate, leading to early after-depolarization in cardiac tissue
[12].
However,
although amiodarone is known to prolong QTc interval, it rarely causes Tdp. A
meta-analysis reported with amiodarone an incidence of Tdp<1.0%[13]. One
explication is that amiodarone also blocks the slow inward calcium current
mediated through the L-calcium channels, and does not increase the QT dispersion
[14].
The risk for amiodarone-induced Tdp greatly increases when other predisposing
conditions are present, such as electrolyte imbalance and concomitant medications
delaying ventricular repolarization
[15].
In this case, the occurrence of Tdp was
associated with the combination therapy of fluoxetine and amiodarone. After
withdrawal of both of them, the QTc interval returned to normal.
Moreover, pharmacokinetic interactions often occur through inhibition of the
cytochrome P450 isoenzyme responsible for metabolizing QTc interval–prolonging
drugs. Amiodarone is a moderate inhibitor of CYP2C9 and CYP2D6, and fluoxetine is
mainly metabolized by the 2C9 and 2D6 isoenzyme. Concomitant use of these agents
may cause an increase in plasma concentration of fluoxetine, which may in turn
increase the risk of QTc interval prolongation. Fayssoil et al.
[16]
reported a case of
Tdp induced by citalopram, one of SSRIs, given in combination with amiodarone.
Thus, we concluded that the combined use of fluoxetine and amiodarone was the
probable cause of the development of recurrent Tdp. Older age and deterioration of
congestive heart failure were likely additional risk factors.
This case report illustrates the importance of considering drug-drug
interactions.
Clinicians
should
closely
monitor
the
ECG
when
QTc
interval-prolonging agents are given to patients with cardiac abnormalities, and
avoid combining 2 QTc interval–prolonging drugs.
Acknowledgment
The authors declare that they have no competing interests.
References
[1] Beach SR, Kostis WJ, Celano CM, Januzzi JL, Ruskin JN, Noseworthy PA,
Huffman JC. Meta-analysis of selective serotonin reuptake inhibitor-associated QTc
prolongation. J Clin Psychiatry. 2014 May; 75(5): e441-e449.
[2] Funk KA, Bostwick JR. A comparison of the risk of QT prolongation among
SSRIs. Ann Pharmacother. 2013 Oct; 47(10): 1330-1341.
[3] Roose SP, Glassman AH, Attia E, Woodring S, Glardina EG, Bigger JT Jr.
Cardiovascular effects of fluoxetine indepressed patients with heart disease. Am J
Psychiatry. 1998 May; 155(5): 660-665.
[4] Isbister GK, Bowe SJ, Dawson A, Whyte IM. Relative toxicity of selective
serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol. 2004; 42(3):
277-285.
[5] Michalets EL, Smith LK, Van Tassel ED. Torsade de pointes resulting from the
addition of droperidol to an existing cytochrome P450 drug interaction. Ann
Pharmacother. 1998 Jul-Aug; 32(7-8): 761-765.
[6] Nykamp DL, Blackmon CL, Schmidt PE, Roberson AG. QTc prolongation
associated with combination therapy of levofloxacin, imipramine, and fluoxetine.
Ann Pharmacother. 2005 Mar; 39(3): 543-546.
[7] Varriale P. Fluoxetine (Prozac) as a cause of QT prolongation. Arch Intern
Med. 2001Feb; 161(4): 612.
[8] Wilting I, Smals OM, Holwerda NJ, Meyboom RH, de Bruin ML, Egberts TC.
QTc prolongation and torsades de pointes in an elderly woman taking fluoxetine. Am
J Psychiatry. 2006 Feb; 163(2): 325.
[9] Deamer RL, Wilson DR, Clark DS, Prichard JG. Torsades de pointes
associated with high dose levomethadyl acetate (ORLAAM). J Addict Dis. 2001; 20(4):
7-14.
[10] Rajamani S, Eckhardt LL, Valdivia CR, Klemens CA, Gillman BM, Anderson
CL, Holzem KM, Delisle BP, Anson BD, Makielski JC, January CT. Drug-induced long
QT syndrome: hERG K+ channel block and disruption of protein trafficking by
fluoxetine and norfluoxetine. Br J Pharmacol. 2006 Nov; 149(5): 481-489.
[11] AI-Khatib SM, LaPointe NM, Kramer JM, Califf RM. What clinicians should
know about the QT interval. JAMA, 2003 Apr 23-30; 289(16): 2120-2127.
[12] Crouch MA, Limon L, Cassano AT. Clinical relevance and management of
drug-related QT interval prolongation. Pharmacotherapy, 2003 Jul; 23(7): 881-908.
[13] Hohnloser SH, Klingenheben T, Singh BN. Amiodarone-associated
proarrhythmic effects: a review with special reference to torsade de pointes
tachycardia. Ann Intern Med. 1994 Oct 1; 121(7): 529-535.
[14] Hii JT, Wyse DG, Gillis AM, Duff HJ, Solylo MA, Mitchell LB. Precordial QT
interval dispersion as a marker of torsade de pointes. Disparate effects of class Ia
antiarrhythmic drugs and amiodarone. Circulation. 1992 Nov; 86(5): 1376-1382.
[15] Lim HE, Pak HN, Ahn JC, Song WH, Kim YH. Torsade de pointes induced by
short-term oral amiodarone therapy. Europace. 2006 Dec; 8(12): 1051-1053.
[16] Fayssoil A, Issi J, Guerbaa M, Raynaud JC, Heroguelle V. Torsade de pointes
induced by citalopram and amiodarone. Ann Cardiol Angeiol (Paris). 2011 Jun; 60(3):
165-168.
Figure 1. (A) ECG on admission (QTc=386ms); (B) ECG showing QT prolongation
(QTc=501ms); (C) The continuous ECG monitoringan episode of Tdp; (D)
Thecontinuous ECG monitoring therelapse of Tdp. (E) ECG showing pacing rhythm
reprogrammed to 90bpm (QTc=493ms). (F) ECG showing pacing rhythm
reprogrammed to 60bpm on discharge (QTc=446ms).
Table 1. Case Reports of QTc Prolongation and Tdp related to fluoxetine.
Source
Age
Sex
Dosage
Tdp Risk
Factors
Concomitant
QT-Prolonging
Medication
Change of QTc (ms)
Before
Tdp
Afte
r
Michalets
EL et al.
1998[5]
59
Female
30mg
daily
Potassium=3
.3 mEq/L,
magnesium=
5.6 mg/dL
Droperidol
and
cyclobenzapri
ne
497
500
440
Nykamp
DL et al.
2005[6]
49
Female
10mg
daily
Potassium=2
.8mEq/L,
Levofloxacin
and
imipramine
／
509
403
Varriale P
et al.
2001[7]
52
Male
20 mg
daily for 2
weeks
followed
by 40 mg
daily for
2.5
months
None
None
380
560
380
Wilting I
et al.
2006[8]
83
Female
20mg
daily
Left bundle
branch block
None
478
/
421
Deamer
RL et al.
2001[9]
41
Female
20mg
daily
Abusing
history (IV
cocaine and
cannabinoid
s);
potassium=4
.5 mEq/L,
magnesium=
1.5 mg/dL
Levomethadyl
/
710
/