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Citalopram induced torsade de pointes, a rare life threatening side effect
Abstract
Acquired Long QT syndrome is a disorder caused by medications, electrolyte imbalances, and drug interactions. This syndrome is associated with an increased risk of a characteristic life-threatening cardiac arrhythmia, known as torsade de pointes (TdP). In the setting of Long QT syndrome (LQTS), selective serotonin reuptake inhibitors (SSRIs) can precipitate TdP. We report the first case of LQTS and TdP induced by citalopram in the United States. After discontinuation of citalopram, the QT/QTc interval normalized after 3 days and resolved further episodes of TdP. Patients on citalopram should be monitored closely for QT/QTc interval to prevent torsade de pointes.
... In Table 1, of the 18 cases of citalopram use resulting in QTc prolongation, 10 were also associated with TdP. 14,[17][18][19]21,[23][24][25] Only one of these cases was a citalopram overdose. 19 Of the 10 cases of TdP, 8 occurred in women. ...
... Favre et al. 12 1 2 1 0 À1 0 0 1 0 1 5 Catalano et al. 13 1 2 1 0 2 0 1 0 0 1 8 Meuleman et al. 14 1 2 1 2 2 0 0 0 0 1 9 Engebretsen et al. 15 1 2 1 0 2 0 1 0 0 1 8 Cuenca et al. 16 1 2 1 0 2 0 0 0 0 1 7 Kourgiannidis et al. 17 1 2 0 0 À1 0 0 0 0 1 3 Blaschke et al. 18 1 2 1 0 À1 0 0 0 0 1 4 Tarabar et al. 19 1 2 1 0 2 0 1 0 0 1 8 Venkatraman et al. 20 1 2 1 0 À1 0 0 0 0 1 4 Kanjanauthai et al. 21 1 2 1 0 2 0 0 0 0 1 7 Bruggisser et al. 22 1 2 1 0 2 0 0 0 0 0 7 Digby et al. 23 1 2 1 0 À1 0 0 0 0 1 4 Fayssoil et al. 24 1 2 1 0 À1 0 0 0 0 1 4 de Gregorio et al. 25 1 2 1 0 À1 0 0 0 0 1 4 Liotier and Coudoré 26 1 2 1 0 2 0 1 0 0 1 8 Deshmukh et al. 27 1 2 1 0 À1 0 0 0 0 1 4 Ibrahim and Omar 28 1 2 1 0 À1 0 0 0 0 1 4 Unterecker et al. 29 1 2 1 0 2 0 1 0 0 1 8 35 Retrospective review ...
Objectives
The aim of this systematic review is to identify case reports of citalopram use resulting in QTc prolongation and/or Torsades de Pointes (TdP) in the medical literature.
Methods
A literature search was conducted of PubMed, MEDLINE, EMBASE, Scopus and PsycINFO databases for case reports published in any language that reported the relationship between citalopram use and the development of QTc prolongation and/or TdP. Also, bibliographic databases of published articles were search for additional cases.
Results
A total of eighteen case reports of citalopram use resulting in QTc prolongation were identified. Of these, ten cases were also associated with the development of TdP. A total of fourteen cases occurred in women and four in men. There were seven cases involving an overdose with citalopram. Of the eighteen cases, twelve occurred in individuals who were < 60 years and six were in individuals who were > 60 years in age. In eight of the eighteen cases, the individuals were taking citalopram between 20 and 60 mg a day. Hypertension was the most common comorbid medical condition as seen in five of the cases.
Conclusions
QTc prolongation and/or Torsades de Pointes (TdP) are infrequent adverse effects associated with citalopram use.
... In addition to the mild transient complaints seen with all SSRIs, citalopram produces seizures and QT prolongation, which ranges from 12% to 68% in case series involving admitted adult patients [9]. Patients have developed torsades de pointes (TdP) with either therapeutic or supratherapeutic doses of citalopram [10][11][12][13]. ...
Selective serotonin reuptake inhibitors (SSRIs) are the most common antidepressants used due to their comparatively less cardiotoxic effects than tricyclic antidepressants. Corrected QT interval (QTc) prolongation is the most common electrocardiography (ECG) change that has been encountered with SSRI overdose. This case report is about a 22-year-old woman who was brought to the emergency department (ED) with an alleged history of consumption of 200 mg of escitalopram. Her ECG showed T-wave inversions in anterior leads one to five, which reverted (in leads four and five) the next day with supportive management. After 24 hours, she developed dystonia, which resolved with mild doses of benzodiazepine. Hence, ECG changes like T-wave inversions may occur even with a small overdose of an SSRI without any significant adverse effects.
... Wydłużanie odstępu Qt poprzez antagonizowanie kanałów potasowych miocytów jest jednym z najpoważniejszych możliwych działań niepożądanych citalopramu. Może wywoływać śmiertelne częstoskurcze nawracające, takie jak torsades de pointes [10][11][12]. rochester i wsp. doszli do wniosku, że citalopram znacznie zwiększa ryzyko zespołu long QT u pacjentów po 60. r.ż. ...
Citalopram to lek znany od ponad 30 lat, obecnie często stosowany jako uzupełnienie przy braku satysfakcjonującej odpowiedzi na monoterapię. Lek ma niewielki potencjał do wchodzenia w interakcje międzylekowe. Jest skuteczny i dobrze tolerowany w zapobieganiu nawrotom depresji u osób starszych.
... These warnings are based on a randomized, double-blind, placebo-controlled multicenter study (12). In addition, some studies with high doses use and some case studies with therapeutic doses has also reported prolongation of the QT interval (30)(31)(32)(33)(34)(35)(36). On the other hand, there are also some studies showing no negative effect on QT interval (37,38). ...
Long QT syndrome (LQTS) is an arrhythmogenic disease with QT prolongation that can cause syncope and sudden death. Citalopram (CIT) may have resulting in LQTS. Omeprazole (OMP) is a CYP2C19 inhibitor. The aim was to investigate the effects of citalopram alone and in combination with omeprazole, on the QT interval and its relationship with the plasma level. Rats were divided groups and treated with 10-30 mg/kg (CIT10/CIT30) citalopram for 1 week and±omeprazole (100 mg/kg/day) from the second week. Plasma levels and ECG were performed.
QT interval was significantly increased in the treatment groups compared to the control group. The plasma level of citalopram in the CIT30 group was significantly higher than that of CIT10 group (p<0.01) and was significantly higher in the CIT10+OMP group than that of the CIT10 group (p<0.01). In treatment groups, the increase in plasma citalopram level correlated positively with the increase in QT (r=0.844, r2=0.713).
In conclusion, it was determined that citalopram caused prolongation of QT interval, the addition of omeprazole increased the length of QT interval and these increases correlated positively with plasma concentration. Therefore, it would be appropriate to routinely measure plasma level in addition to ECG, particularly in patients with additional risk factors.
Key Words: Citalopram, EKG, radiotelemetry, omeprazol, LQTS, TDM
... A total of 16 publications were included (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). The main criterion for inclusion of articles was that they had an admission ECG, either with given QRS and QTc values or with attached ECG-files that enabled us to calculate these parameters. ...
Background
The U.S. Food and Drug Administration (FDA) has stated that citalopram and escitalopram should not be used at daily doses above 40 mg/20 mg due to risk for development of fatal ventricular arrhythmias like torsade de pointes (TdP). Yet, supratherapeutic serum concentrations of citalopram are common and predicting patients at risk for TdP is of high clinical value. Accordingly, we investigated whether QRS/QTc; developed for predicting TdP in hypothermic patients could be used in citalopram intoxication.MethodsA total of 16 publications describing patients suffering from complications due to citalopram or escitalopram treatment, or intoxication with the same substances, were included after a systematic search. The main criterion for inclusion was admission ECG, either with given QRS and QTc values or with attached ECG-files that enabled calculation.ResultsQRS/QTc rather that QTc alone emerged as a marker of ventricular arrhythmia in the 16 included case reports, with highly significant (p < 0.0005) lower values in patients displaying ventricular arrhythmias.Conclusion
Citalopram and escitalopram are extensively used in treatment of depressive disorders, and a large proportion of patients have supratherapeutic serum concentrations. Calculation of QRS/QTc in available case reports show that this novel ECG-marker has potential to predict patients at risk for developing ventricular arrhythmias.
... In both cases, the QTc interval normalized upon discontinuation of the agents. 26,27 Serotonin norepinephrine reuptake inhibitors Serotonin norepinephrine reuptake inhibitors (SNRIs) are typically used as second-line agents in the management of geriatric depression, and can be used for management of neuropathic pain. ...
... In both cases, the QTc interval normalized upon discontinuation of the agents. 26,27 Serotonin norepinephrine reuptake inhibitors Serotonin norepinephrine reuptake inhibitors (SNRIs) are typically used as second-line agents in the management of geriatric depression, and can be used for management of neuropathic pain. ...
Antidepressants are widely used medications for a range of medical conditions such as mood disorders and chronic pain in older adults. A vast body of evidence exists concerning the risks of QT interval prolongation associated with these agents and healthcare providers should critically evaluate the potential for QT prolongation when selecting antidepressant agents. Long QT syndrome is a disorder of myocardial repolarization that manifests as a prolonged QT interval on an electrocardiogram (ECG) and has been demonstrated to increase with age. The objective of this review is to present and evaluate existing literature regarding the risk of QT prolongation in older adults, age 60 years and older, and discuss the implications for clinical practice. A PubMed search was conducted to identify studies evaluating the QT prolonging effects of antidepressant medications and publications were chosen based on pertinent criteria. Depending on the antidepressant agent and patient-specific factors, clinicians should assess and monitor electrolytes and EGCs to evaluate the risks and benefits for older adults receiving agents known to prolong the QT interval.
... clozapine, olanzapine) @BULLET Antispasmodics for urinary incontinence (e.g. oxybutynin) @BULLET Histamine (H 1 ) antagonists (particularly first generation, such as diphenhydramine) @BULLET Histamine (H 2 ) antagonists (GI agents, such as cimetidine, ranitidine) @BULLET Muscle Relaxants: pancuronium @BULLET Tricyclic Antidepressants (particularly tertiary) @BULLET Tropane Alkaloids: scopolamine, hyoscyamine, atropine QTc prolongation can be dose related as seen with thioridazine, ziprasidone and citalopram [9, 43, 44]. Therefore, PK interactions which increase the concentration of these drugs are particularly concerning and will be discussed later in the chapter. ...
Over the past 20 years the number of psychotropic medications has increased dramatically. As a result, the use of psychotropic polypharmacy has rapidly expanded. One outcome of psychotropic polypharmacy has been an increase in the number of drug interactions that occur in routine clinical practice. Although drug interactions resulting in death are rare, the effects of drug interactions are often misinterpreted as drug inefficacy or toxicity. Therefore an understanding of pharmacodynamic and pharmacokinetic drug interactions is essential when using polypharmacy. This chapter reviews the mechanisms of drug interactions, describes the most commonly seen drug interactions and offers suggestions for addressing drug interactions in clinical practice. Given polypharmacy is common in psychiatry; clinicians must routinely assess which medication combinations are safe to prescribe, require dose adjustments and are best avoided. Future research should focus on the role of genetics and interventions to decrease adverse drug reactions related to drug interactions.
... Tricyclics, while effective, have strong anticholinergic action and should be used cautiously. They also have more QTc prolonging side effect, as does the SSRI, citalopram (Rasmussen et al. 1999 ;Catalano et al. 2001 ;Kanjanauthai et al. 2008 ). ...
Intensive Care Units, and acute medical conditions seen in such settings are associaed with acute stress and various psychiatric and psychological conditions. They include, delirium in the ICU, and the role of defense and coping mechanisms and personality. Psychiatric aspects of heart disease, stroke, and seizures are discussed.
... The authors suggested that active transporters (the "blood-brain barrier") had protected the brain. 31 ...
Recent antidepressant side effects of particular interest have included bleeding risk, and effects during pregnancy and the neonatal period. While increased bleeding risk with serotonergic antidepressants has been recognised for many years, the incidence and severity of this have been uncertain—issues of particular pertinence to patients having surgical procedures. Recent large cohort studies and meta-analyses have focused on perioperative bleeding in general (and hip surgery in particular), the impact of co-prescription with anticoagulants, gastrointestinal bleeding, brain hemorrhage and post-partum hemorrhage. There has also been increasing data clarifying the safety of antidepressants during pregnancy and the perinatal period, with studies on spontaneous abortion and miscarriage, teratogenic risk (in particular cardiac and neurological), preterm and low birth weight, neonatal adaptation, and infant development (including potential risk to autism and ADHD). Other areas covered by recent reports include effects on cardiac function, bone mineral density and fracture risk, as well as suicide potential and unusual GIT effects.
... 52, p 683 Citalopram was associated with a significantly greater QTc increase than placebo, and more people in the citalopram group showed a QTc increase greater than 30 ms. 52,53 Citalopram, at high doses, can induce potentially fatal cardiac arrhythmias, especially when combined with certain other drugs. [54][55][56][57][58][59] Other SSRIs ...
To assess older age and female sex, 2 of the major risk factors for potentially fatal cardiac arrhythmias or sudden cardiac death in patients prescribed psychotropics, within the context of electrocardiographic evidence of time between start of Q wave and end of T wave (QT) interval prolongation, which is an indicator of an increased risk for potentially fatal cardiac arrhythmias.
The literature on the relation between age, sex, and QT interval with respect to psychotropic drugs was reviewed.
The QT interval must be corrected (QTc) for heart rate. Because slower heart rates prolong and faster heart rates shorten the QT interval, people with faster heart rates may have a prolonged QT interval that is not apparent until the correction is performed. QTc values for apparently healthy post-pubertal people are less than 450 ms for males and less than 470 ms for females. The longer QT intervals in women may account for their increased risk of potentially fatal cardiac arrhythmias on psychotropics. QTc increases with increasing age. Assessment of QTc in older people is especially important to identify people with a longer QTc who are more likely to attain a serious QT level with drugs that prolong QTc. The age-related increase in QTc is more evident in men than women, suggesting that male sex does not afford protection against potentially fatal arrhythmias at older age.
The association of increasing age and female sex with greater QT intervals indicates the need to have an increased awareness of the QTc prior to use of these psychotropics and to evaluate the QTc after initiation of therapy.
... Most of the selective serotonin-reuptake inhibitors have been reported to prolong the QT interval, occasionally resulting in the onset of torsade de pointes (de Boer et al., 2005;Kanjanauthai et al., 2008;Kogut et al., 2013;Singh and Maldonado-Duran, 2014;Wenzel-Seifert et al., 2011;Wilting et al., 2006), suggesting that the potential of induction of long QT syndrome by fluvoxamine may be class effects of selective serotonin-reuptake inhibitor. Meanwhile, common chemical structures responsible for inhibiting I Kr channel have been reported (Carlsson et al., 1997;Sugiyama and Hashimoto, 1998), in which a substituted phenyl ring is connected to a basic amine via a highly variable linking group, the distance between the phenyl ring and the basic amine seems to be of critical importance for a high I Kr blocking potency; and 3 to 4 atoms are considered to be optimum. ...
Fluvoxamine is one of the typical selective serotonin-reuptake inhibitors. While its combined use with QT-prolonging drugs has been contraindicated because of the increase in plasma concentrations of such drugs, information is still limited whether fluvoxamine by itself may directly prolong the QT interval. We examined electropharmacological effects of fluvoxamine together with its pharmacokinetic profile by using the halothane-anesthetized dogs (n = 4). Fluvoxamine was intravenously administered in three escalating doses of 0.1, 1 and 10 mg/kg over 10 min with a pause of 20 min between the doses. The low dose provided therapeutic plasma drug concentration, whereas the middle and high doses attained approximately 10 and 100 times of the therapeutic ones, respectively. Supra-therapeutic concentration of fluvoxamine exerted the negative chronotropic, inotropic and hypotensive effects; and suppressed the atrioventricular nodal and intraventricular conductions, indicating inhibitory actions on Ca2+ and Na+ channels, whereas it delayed the repolarization in a reverse use-dependent manner, reflecting characteristics of rapidly activating delayed rectifier K+ current channel-blocking property. Fluvoxamine prolonged the terminal repolarization phase at 100 times higher concentration than the therapeutic, indicating its proarrhythmic potential. Thus, fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations.
... We found 16 case reports of citalopram-induced QTc prolongation and/or TdP (Supplementary Table 11 and Table 7) [69,87,112,[168][169][170][171][172][173][174][175][176][177][178][179][180]. All patients had at least one additional risk factor for QTc prolongation besides therapeutic doses of citalopram. ...
We comprehensively reviewed published literature to determine whether it supported the link between corrected QT (QTc) interval prolongation and torsade de pointes (TdP) for the 11 second-generation antipsychotics and seven second-generation antidepressants commonly implicated in these complications. Using PubMed and EMBASE, we identified four thorough QT studies (one each for iloperidone, ziprasidone, citalopram, and escitalopram), 40 studies specifically designed to assess QTc interval prolongation or TdP, 58 publications based on data from efficacy and safety trials, 18 toxicology studies, and 102 case reports. Thorough QT studies, QTc prolongation-specific studies, and studies based on efficacy and safety trials did not link drug-associated QTc interval prolongation with TdP. They only showed that the drugs reviewed caused varying degrees of QTc interval prolongation, and even that information was not clear and consistent enough to stratify individual drugs for this risk. The few toxicology studies provided valuable information but their findings are pertinent only to situations of drug overdose. Case reports were most informative about the drug-QTc interval prolongation-TdP link. At least one additional well established risk factor for QTc prolongation was present in 92.2 % of case reports. Of the 28 cases of TdP, six (21.4 %) experienced it with QTc interval <500 ms; 75 % of TdP cases occurred at therapeutic doses. There is little evidence that drug-associated QTc interval prolongation by itself is sufficient to predict TdP. Future research needs to improve its precision and broaden its scope to better understand the factors that facilitate or attenuate progression of drug-associated QTc interval prolongation to TdP.
... Female sex, age, sertraline, sotalol and heart disease #7 [Blaschke et al. 2007] 77-year-old woman Citalopram 20 mg 490 Female sex, age, bradycardia, citalopram, risperidone, cotrimoxazole, chronic medical disease and heart disease #8 [Kanjanauthai et al. 2008] 81-year-old man Citalopram (assumed to be 20 mg) ...
Objective:
In the light of the recent United States Food and Drug Administration (FDA) warning to clinicians on using previously approved doses of citalopram because of the purported higher risk of torsade de pointes (TdP), we pursued the broader question: are selective serotonin reuptake inhibitor (SSRI) antidepressant agents as a group unsafe because they might induce QTc interval prolongation and TdP?
Method:
We reviewed the literature and found only 15 case reports (6 of fluoxetine, 1 of sertraline and 8 of citalopram) of SSRI-associated QTc interval prolongation linking to TdP.
Results:
A total of 13 cases contained sufficient information for analysis. In the setting of TdP, QTc interval prolongation does not clearly relate to SSRI dose.
Conclusion:
Applying conventional statistics as the FDA does may not be the best tool to study this phenomenon because SSRI-associated TdP is a very rare event and hence best understood as an 'extreme outlier'. Despite the limitations inherent in case report material, case reports on drug-associated QTc interval prolongation and TdP provide valuable information that should be considered along with other sources of information for clinical guidance.
... One advantage of this group of antidepressants is that they appear to be relatively safe when compared with older classes of antidepressants. Nevertheless, several cases related to resultant QT prolongation from overdoses of selective SSRIs such as fluoxetine, sertraline, and citalopram have been reported [1,7]. In fact, both citalopram and fluoxetine have been shown to pharmacologically inhibit cardiac potassium channel current, which is imperative for normal ventricular repolarization. ...
We present a case of drug-induced QT prolongation caused by an escitalopram overdose in a patient with previously undiagnosed congenital LQTS. A 15-year-old Caucasian female presented following a suicide attempt via an escitalopram overdose. The patient was found to have a prolonged QT interval with episodes of torsades de pointes. The patient was admitted to the telemetry unit and treated. Despite the resolution of the torsades de pointes, she continued to demonstrate a persistently prolonged QT interval. She was seen by the cardiology service and diagnosed with congenital long QT syndrome. This case illustrates the potential for an escitalopram overdose to cause an acute QT prolongation in a patient with congenital LQTS and suggests the importance of a screening electrocardiogram prior to the initiation of SSRIs, especially in patients at high risk for QT prolongation.
... Auch Einzelfälle von ausgeprägten Bradykardien unter klinischen Standarddosen wurden beobachtet (Isbister et al., 2001). Der erste Fall von Torsade de Pointes unter Citalopram wurde 2008 berichtet (Kanjanauthai et al., 2008). Das QTc-Intervall scheint mit der Ci- talopram-Plasmakonzentration zu korrelieren (Unterecker et al., 2011 ). ...
... It has been suggested that selective serotonin reuptake inhibitors (SSRIs) might ameliorate the adverse effect of depression on cardiovascular disease through the inhibition of platelet aggregation, even independently of changes in depression [12] . This potential benefit, however, is counteracted by recognized adverse cardiovascular side effects [13][14][15] . In particular, the use of SSRIs such as citalopram and escitalopram is associated with cases of arrhythmias and prolonged QTc interval on electrocardiogram in patients lacking cardiovascular disorders [16] . ...
... Patients with functional bowel disorders undergo substantially more unnecessary abdominal and pelvic surgery than the general population ( 1,2 ). Such patients are also more likely to undergo fruitless endoscopic retrograde cholangiopancreatography, endoscopic ultrasound, and optical endoscopy ( 3,4 ). Aft er such interventions, an appreciable fraction of patients enter the vicious cycle, wherein postoperative ileuses, adhesions, or infections lead to future stress, pain, and anxiety, which lead to further diagnostic and therapeutic interventions, initiating a lamentable fractal outgrowth of cost and pain ( 2 ). ...
The American Journal of Gastroenterology is published by Nature Publishing Group (NPG) on behalf of the American College of Gastroenterology (ACG). Ranked the #1 clinical journal covering gastroenterology and hepatology*, The American Journal of Gastroenterology (AJG) provides practical and professional support for clinicians dealing with the gastroenterological disorders seen most often in patients. Published with practicing clinicians in mind, the journal aims to be easily accessible, organizing its content by topic, both online and in print. www.amjgastro.com, *2007 Journal Citation Report (Thomson Reuters, 2008)
... A number of clinical reports describe the occurrence of QT prolongation in patients receiving citalopram. For example, an Author's personal copy 81-year-old man was found to have prolonged QT (572 ms) and QTc (695 ms) and developed torsades de pointes; the ECG normalised within 3 days of discontinuing citalopram [12] . A 47-year-old woman with pre-existing dilated cardiomyopathy developed sinus bradycardia and prolonged QT interval (463 ms) that was attributed to a recent dose increase from citalopram 20 mg to 40 mg daily; the ECG restored to normal within 24 h [13]. ...
Purpose:
Citalopram is a selective serotonin reuptake inhibitor (SSRI) antidepressant that is widely used in clinical practice. Recent data have indicated that high therapeutic citalopram doses may cause electrocardiographic abnormalities, and the regulatory authorities have amended its licenced dosage. The present manuscript reviews the available data concerning citalopram and cardiac toxicity.
Methods:
Published data concerning the cardiac effects of citalopram were ascertained, and clinical data were considered separately between adverse effects arising from therapeutic use versus toxicity in the setting of intentional overdose.
Results:
The occurrence of electrocardiographic abnormalities has long been recognised as a complication of acute citalopram overdose; a dose-effect relationship for QT prolongation has been described in a number of large case series, including several cases of torsades de pointes. In contrast, few data indicate the occurrence of QT prolongation and arrhythmia after therapeutic doses, and a dose-effect relationship within the therapeutic range has only recently been established. Citalopram is more likely to cause QT prolongation in patients with metabolic disturbance or pre-existing cardiac disease.
Conclusions:
A dose-effect relationship for QT prolongation exists across a broad range of citalopram doses, such that caution must be exercised when prescribing high doses or if there are co-existent risk factors for QT effects. The available data illustrate how clinical toxicity data may offer an earlier signal of cardiac effects than ascertained from conventional pharmacovigilance methods.
... 73 A further report indicates that therapeutic citalopram administration caused severe prolongation of QT and QTcB (572 msec and 695 msec, respectively) in a female patient who developed TdP; the QTcB normalized 3 days after citalopram discontinuation. 74 Escitalopram, the S-enantiomer of citalopram, has been reported to cause significant reversible QTcB prolongation, even after only two daily administrations of 5 mg. 75 Data from a thorough QT study was recently presented by regulatory authorities showing a dose-dependent increase in QTcB and QTcF within the therapeutic range. ...
A number of different psychotropic agents have been associated with an increased risk of cardiovascular disease, and these relationships have been difficult to interpret due to the presence of confounding factors. Recently, there has been renewed interest in the potential for certain antidepressants to cause QT prolongation, which is a predisposing factor for arrhythmia. However, the optimum means of determining QT remains contentious due to discrepancies between methods that may be readily applied in a clinical setting versus more detailed techniques during regulatory assessment. A number of different pharmacological mechanisms might explain the occurrence of adverse cardiac effects, and these differ according to the type of antidepressant agent. Emerging data indicate that citalopram exhibits a dose-effect relationship for QT prolongation. Whereas cardiotoxicity is readily apparent in the context of intentional antidepressant overdose, the occurrence of cardiac effects as a result of therapeutic administration is less certain. Pre-existing cardiac disease and other factors that independently predispose to arrhythmia are important considerations. Therefore, clinical judgment is needed to evaluate the overall risk or benefit of a particular antidepressant in any patient. Close monitoring should be considered for those at greatest risk of QT prolongation and arrhythmia.
... Case Report #3. 21 The main risk factors contributing to torsade de pointes were advanced age, severe medical illnesses, and citalopram administration. When citalopram was stopped, QTc interval prolongation and torsade de pointes resolved. ...
Recently, both the manufacturer of citalopram and the US Food and Drug Administration have warned health care providers and patients about new information implicating drug-induced QTc interval prolongation and torsade de pointes when using citalopram in doses >40 mg/day. This warning is not placed in the context of either benefits or risks in real-world clinical practice, leaving clinicians with an untenable choice between depriving patients of high-dose citalopram or malpractice litigation. We reviewed the literature and found no cases of citalopram-induced sudden cardiac death among patients taking up to 60 mg/day of citalopram and free of risk factors for QTc interval prolongation and torsade de pointes. Because psychotropic drug-induced sudden cardiac death is an outlier in the absence of identified risk factors for QTc interval prolongation and torsade de pointes, we do not believe current Phase 3 and Phase 4 studies provide sufficient information to limit current prescribing practices for citalopram (20 mg to 60 mg/day). We urge drug manufacturers and regulatory agencies to periodically publish full case reports of psychotropic drug-induced QTc interval prolongation, torsade de pointes, and sudden cardiac death so that clinicians and investigators may better understand the clinical implications of prescribing such drugs as citalopram.
... 9 Cases have been reported of citalopram-induced torsades de pointes in patients with end-stage renal disease or abnormal electrolyte lev- els. 10,11 However, the torsades de pointes in our patient occurred in the absence of overdose, electrolyte imbal- ance, and renal or liver failure. We suspect that she had concealed LQTS, which was unmasked by citalopram. ...
Citalopram is a selective serotonin reuptake inhibitor with a favorable cardiac-safety profile. Corrected QT interval (QTc) prolongation and cardiac arrhythmias have not been previously reported in association with citalopram use except in the presence of overdose, abnormal electrolyte values, or renal or liver failure. Herein, we report the case of a 40-year-old woman with mental depression who presented with a prolonged QTc interval and torsades de pointes after the initiation of citalopram at therapeutic doses. The QTc interval improved when citalopram therapy was discontinued. We recommend that clinicians investigate the family history for sudden deaths and perform baseline electrocardiography before prescribing citalopram. We also recommend routine electrocardiographic testing during citalopram therapy, and that patients with long QT syndrome avoid taking citalopram.
Patients with cancer are prone to prolongation of the corrected QT interval (QTc) due to the use of anticancer drugs with QTc-prolonging potential in combination with electrolyte imbalances caused by, for example, gastrointestinal side-effects. However, most anticancer drugs were approved with little information on their QTc-prolonging potential and the added risk of torsade de pointes. The absence of this information on the drug label poses a considerable challenge to clinicians regarding the measures that need to be taken to safely start anticancer treatment. In this Review, we provide a comprehensive overview of the evidence for the QTc-prolonging properties of 205 anticancer drugs and 14 antiemetic drugs available from drug labels, assessment reports, and published studies. We classify the drugs as low-risk, moderate-risk, or high-risk for QTc prolongation. We also discuss the clinical relevance of these findings and include practical recommendations to guide clinicians to select the drugs with the least QTc-prolonging properties and to adequately monitor susceptible patients.
Background:
Individuals receiving maintenance hemodialysis may be particularly susceptible to the lethal cardiac consequences of drug-induced QT prolongation because they have a substantial cardiovascular disease burden and high level of polypharmacy, as well as recurrent exposure to electrolyte shifts during dialysis. Electrophysiologic data indicate that among the selective serotonin reuptake inhibitors (SSRIs), citalopram and escitalopram prolong the QT interval to the greatest extent. However, the relative cardiac safety of SSRIs in the hemodialysis population is unknown.
Methods:
In this retrospective cohort study, we used data from a cohort of Medicare beneficiaries receiving hemodialysis included in the US Renal Data System registry (2007-2014). We used a new-user design to compare the 1-year risk of sudden cardiac death among hemodialysis patients initiating SSRIs with a higher potential for prolonging the QT interval (citalopram, escitalopram) versus the risk among those initiating SSRIs with lower QT-prolonging potential (fluoxetine, fluvoxamine, paroxetine, sertraline). We estimated adjusted hazard ratios using inverse probability of treatment weighted survival models. Nonsudden cardiac death was treated as a competing event.
Results:
The study included 30,932 (47.1%) hemodialysis patients who initiated SSRIs with higher QT-prolonging potential and 34,722 (52.9%) who initiated SSRIs with lower QT-prolonging potential. Initiation of an SSRI with higher versus lower QT-prolonging potential was associated with higher risk of sudden cardiac death (adjusted hazard ratio, 1.18; 95% confidence interval, 1.05 to 1.31). This association was more pronounced among elderly individuals, females, patients with conduction disorders, and those treated with other non-SSRI QT-prolonging medications.
Conclusions:
The heterogeneous QT-prolonging potential of SSRIs may differentially affect cardiac outcomes in the hemodialysis population.
Renal patients have a high incidence of adverse drug reactions due to both pharmacokinetic and pharmacodynamic changes and detecting these adverse drug reactions relies heavily on having a high index of suspicion—which seems to be invoked through experience, whether our own or that of our colleagues. Pharmacists must be vigilant about adverse drug reactions and it is vital that pharmacists continue to teach their colleagues about their experiences identifying less common adverse drug reactions and adverse drug reactions with unusual presentations in addition to simply reporting these adverse drug reactions.
While many drugs have some effect on serotonergic receptors this chapter focuses upon the toxicity seen with medications whose primary antidepressant therapeutic mechanism of action is to modify serotoninergic transmission. This includes selective serotonin reuptake inhibitors (SSRI), serotonin noradrenergic reuptake inhibitors (SNRI), and tetracyclic and triazolopyridine antidepressants (Tables 1, 2, 3, and 4).
While
many drugs have some effect on serotonergic receptors this chapter focuses upon the toxicity seen with medications whose primary antidepressant therapeutic mechanism of action is to modify serotoninergic transmission. This includes selective serotonin reuptake inhibitors (SSRI), serotonin noradrenergic reuptake inhibitors (SNRI), and tetracyclic and triazolopyridine antidepressants (Tables 1, 2, 3, and 4).
A systematic review was conducted for all published case reports on drug-induced torsade de pointes (TdP) in elderly (≥80 years) patients to study if the administration of the offending agent was reckless. Overall, 61 reports on drug-induced TdP in patients aged 80-97 years were included in the analysis. Non-modifiable risk factors for drug-induced TdP (e.g. acute coronary syndrome, female gender and congestive heart failure), modifiable risk factors (e.g. hypokalemia, severe hypomagnesemia and digitalis toxicity) and reckless administration of a QT interval-prolonging agent (e.g. despite a known QT interval prolongation or a history of TdP, together with other QT interval prolonging agents in higher than recommended doses) were recorded in each case. Overall, 54 (88.5%) patients had non-modifiable risk factors for drug-induced TdP and 21 (34.4%) patients had modifiable risk factors. The administration of the offending agent was reckless in one half (n = 31; 50.8%) of the patients. The most prevalent reckless administration of a QT interval-prolonging agent was together with other QT interval-prolonging agents (n = 16; 51.6%) or despite QT interval prolongation (n = 8; 25.8%). In conclusion, although risk factors for drug-induced TdP are prevalent in elderly patients with drug-induced TdP, in approximately 50% of patients it appeared following a reckless administration of a QT interval-prolonging agent. In this population physicians should particularly avoid administration of two or more QT interval-prolonging agents simultaneously or administration of a QT interval-prolonging agent despite QT interval prolongation.
Introduction:Recently, controversy has surrounded a 2011 Food and Drug Administration warning against using citalopram at doses >40 mg/day due to QTc prolonging effects.
Methods:Patients ≥18 years old at the VA North Texas Health Care System were included in this retrospective review if they had received at least 1 prescription for a 30-day supply of citalopram between January 1, 2007, and February 29, 2012, and had a baseline electrocardiogram (ECG) within 1 year before initiation or dose increase of citalopram and at least 1 repeat ECG within 3 months after citalopram initiation or dose increase. The primary endpoint was the prevalence of QTc prolongation (QTc interval ≥470 ms for men and ≥480 ms for women) after initiation or a dose increase of citalopram. For secondary objectives, Fisher exact tests were used determine if there was a dose-dependent difference in prevalence of QTc prolongation among the whole study sample and among the subgroup of patients ≥60 years old.
Results:Among the entire study sample, QTc prolongation was identified in 12 patients (16.4%) after initiation or a dose increase of citalopram. In the subgroup of patients ≥60 years old, QTc prolongation was identified in 7 patients (21.9%). Prevalence of QTc prolongation increased with dose in the entire study population (P = .016) and in patients ≥60 years (not significant).
Discussion:This retrospective study suggests that citalopram produces a dose-dependent increase in QTc interval.
Typical consult question “Please evaluate and treat this twenty-five year old pregnant female with a history of depression, currently in the second trimester of an unplanned pregnancy, who stopped her antidepressant medication at the time of a positive pregnancy test.” Depression is a significant public health problem that disproportionately affects women, often during the childbearing years. Perinatal depression, which refers to depression during both pregnancy and the post-partum period, is common, particularly in low-income and ethnic minority populations. It is associated with adverse consequences for the mother, infant, and other family members and often goes undetected and untreated. Depression during the perinatal period is associated with assessment and treatment challenges requiring unique collaboration between patient and maternal and child health and mental healthcare providers. Background Epidemiology of depression during pregnancy and the post-partum period Although many women and their providers still believe that pregnancy “protects” women from experiencing depression, research studies show that it is widespread. In the obstetric clinic setting, nearly 40% of women are identified with a mental health disorder, most commonly depression. The prevalence of antenatal depression in the community is approximately 10%, but may be as high as 27.6% among women in poor urban communities. Post-partum depression is also common, with around 13% of women meeting criteria for major or minor depression.
Introduction Consultation psychiatrists are skilled clinicians and expert liaisons in the general hospital setting. In their roles as “med-psych detectives,” consultation psychiatrists are called upon to assist in complex cases and to interact with primary teams, nursing teams, ancillary services, and patients and family members. They investigate medical/psychiatric interactions, assess psychiatric symptoms, and offer treatment recommendations. Communication is the most crucial element of the consultation process. Clear communication improves the process of your consultation as well as the result, by ensuring accurate, timely, and helpful interventions. This chapter strives to give residents the tools necessary to enter the world of consultation-liaison psychiatry. First steps Institutional and personal organization As a member of the psychiatric consultation team, you must know your role and maintain your identity in your institution. Who are the members of your team? Who carries the consult pager? What consults are appropriate for you to see (adult, pediatric, emergency room, other)? With whom do you staff new evaluations? Being organized and having the requisite tools will prepare you to perform the duties expected of you (Table 1.1). Carry necessary items with you, and know where to access other information when needed. Finally, as noted by Wise and Rundell, “Wear a white coat – on your shoulders and in your brain”. Your role as a medical practitioner should be clearly and visibly evident to those who consult you, as well as to the patients you see.
Several classes of recreational and prescription drugs have been associated with an increased risk of cardiovascular disease and the occurrence of arrhythmias, which may be involved in sudden deaths in chronic users even at therapeutic doses. The study presented herein focuses on pathological changes involving the heart, which may be caused by selective serotonin reuptake inhibitor use and their possible role in the occurrence of sudden cardiac death. A total of 40 cases were included in the study and were divided evenly into 2 groups: 20 cases of patients treated with selective serotonin reuptake inhibitors and 20 cases of sudden deaths involving patients void of any drug treatment. The first group included 16 patients treated with citalopram and 4 with sertraline. Autopsies, histology, biochemistry, and toxicology were performed in all cases. Pathological changes in selective serotonin reuptake inhibitor users consisted of various degrees of interstitial and perivascular fibrosis as well as a small degree of perineural fibrosis within the myocardium of the left ventricle. Within the limits of the small number of investigated cases, the results of this study seem to confirm former observations on this topic, suggesting that selective serotonin reuptake inhibitors may play a potential, causative role in the pathogenesis of sudden deaths in chronic users even at therapeutic concentrations.
CME Educational Objectives
1. Describe the basic cardiophysiology of QT prolongation and how psychotropic medication can affect it.
2. Understand the role that each class of drugs plays in the potential of QT prolongation.
3. Apply the principles to clinical practice in order to assure patient safety.
Prolongation of QTC is an electrocardiographic finding indicating prolongation of cardiac repolarization, which increases the risk for torsades de pointes, a form of ventricular tachycardia that can lead to sudden cardiac death. Sudden cardiac death in the setting of antipsychotic treatment was first described in the 1960s with thioridazine; since that time, many other psychotropic medications have been associated with QTc prolongation. This article reviews the electrophysiology of the cardiac cycle and the mechanism of QTc prolongation. Each major class of psychotropic medications also is reviewed, focusing on its propensity to prolong QTc and association with torsades de pointes (TdP) and sudden cardiac death. Other risk factors for TdP are also discussed. Examination of the management and treatment of QTc prolongation and TdP aims to assist the clinician with an approach to patients receiving psychotropic medications.
Recently, Forest Laboratories warned about QTc prolongation associated with the use of citalopram. After these reports, the FDA warned that citalopram should no longer be used at doses greater than 40 mg/day for patients ≤ 60 years of age or greater than 20 mg/day in patients over 60 years of age. As a result, providers and formulary managers were advised to reevaluate the use of citalopram to conform to current FDA guidelines. Clinicians have the option to: (1) maintain the patient on the current dose (no change), document that the current EKG (with QTc) is within a normal range and inform the patient of the current recommendations or (2) change the therapy, which consists of either a dose reduction or change to an alternate agent. It may be appropriate to keep a patient on current therapy above the FDA recommended maximum if proper documentation is maintained (e.g., past history of severe depression, normal EKG). Citalopram should be discontinued in patients who have persistent QTc measurements greater than 500 ms.
The American Journal of Gastroenterology is published by Nature Publishing Group (NPG) on behalf of the American College of Gastroenterology (ACG). Ranked the #1 clinical journal covering gastroenterology and hepatology*, The American Journal of Gastroenterology (AJG) provides practical and professional support for clinicians dealing with the gastroenterological disorders seen most often in patients. Published with practicing clinicians in mind, the journal aims to be easily accessible, organizing its content by topic, both online and in print. www.amjgastro.com, *2007 Journal Citation Report (Thomson Reuters, 2008)
The American Journal of Gastroenterology is published by Nature Publishing Group (NPG) on behalf of the American College of Gastroenterology (ACG). Ranked the #1 clinical journal covering gastroenterology and hepatology*, The American Journal of Gastroenterology (AJG) provides practical and professional support for clinicians dealing with the gastroenterological disorders seen most often in patients. Published with practicing clinicians in mind, the journal aims to be easily accessible, organizing its content by topic, both online and in print. www.amjgastro.com, *2007 Journal Citation Report (Thomson Reuters, 2008)
Prolongation of the corrected QT (QTc) interval is a key issue for patients who receive psychotropic medications. Such patients may have baseline clinical risk factors for QTc prolongation, and many psychotropic medications may further prolong this interval. This has great clinical relevance, as QTc prolongation is linked with dangerous arrhythmias, especially torsades de pointes (TdP).
We summarize current literature regarding appropriate methods of calculating the QTc interval, the association of the QTc interval with TdP, and risk factors for QTc prolongation. We then review connections between psychiatric medications and QTc prolongation, with a specific focus on antidepressants and antipsychotics.
QTc interval prolongation is an established, though imperfect, risk marker for TdP. There are no well-controlled studies that assess the risk of TdP associated with psychotropic agents. There are limited data that selective serotonin reuptake inhibitors (SSRIs) as a class are linked to QTc prolongation; citalopram appears more likely than others to induce this phenomenon. Among antipsychotics, thioridazine remains the agent most associated with QTc prolongation; intravenous haloperidol also appears to carry an increased risk. Of the atypical antipsychotics, ziprasidone appears most likely to prolong the QTc interval.
The majority of patients in need of psychotropic medications display few risk factors for QTc prolongation and should be considered to be at low risk for TdP. The frequency of cardiac monitoring for patients receiving psychiatric medications should be individually determined, based on the prescribed agent(s) and additional risk factors for TdP.
The use of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors in treating depression, mood disorders, and behavioral disorders has escalated dramatically in the last 20 years, resulting in increased risk and clinical presentation of serotonin toxicity. Health care providers must also be aware of other medications and substances with proserotonergic activity that can cause serotonin toxicity when used in combination with these medications. There are many adverse effects of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, although their toxicity profile compared to older antidepressants seems to be safer. Serotonin syndrome is described as a clinical triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. It encompasses a spectrum of clinical findings ranging from a few nonspecific symptoms to significant clinical toxicity that can result in death. The objectives of this article are to review specific serotonergic medications including their adverse effects and toxicity in overdose, to describe other medications/substances that have proserotonergic effects, which could result in serotonin excess in combination with traditional serotonergic agents, and to define the criteria for serotonin syndrome/toxicity and its treatment.
In adults, citalopram is more likely to cause seizures and ECG changes than other selective serotonin reuptake inhibitors (SSRIs). Data in children are lacking, yet the 2007 American Association of Poison Control Centers out-of-hospital citalopram consensus guideline mirrors the guideline for other SSRIs.
To compare the clinical effects and hazard index of citalopram with other SSRIs in pediatric ingestions.
An 11-year retrospective analysis of national poison center data was conducted. Acute, known-type SSRI ingestions in children younger than 6 years with known outcome were included. Clinical effects and hazard index (number of major or fatal outcomes/1000 SSRI ingestions) were compared. Citalopram dose-response was evaluated.
The 35 296 included cases by SSRI type were citalopram (3747), escitalopram (4815), fluoxetine (5946), fluvoxamine (273), paroxetine (7157), and sertraline (13 358). The overall hazard index was 0.340. The hazard index for citalopram (0.801) was 2.8-fold higher than for non-citalopram SSRIs (0.285). Comparing seizures (single or multiple discrete) and cardiac effects (conduction disturbances, other ECG changes or other dysrhythmia) of citalopram with the other SSRIs, pediatric citalopram ingestions were more likely to develop seizures (5 of 3747 [0.13%] vs. 10 of 31 549 [0.03%], OR = 4.2; 1.4-12.3) and cardiac toxicity (9 of 3747 [0.24%] vs. 25 of 31 549 [0.08%], OR = 3.0; 1.4-6.5). Clinical effects occurring more frequently with other SSRIs included tachycardia (p = 0.0236), oral irritation (p = 0.0412), vomiting (p = 0.0036), agitation/irritability (p = 0.0104), and hyperthermia (p = 0.0314). There was a dose response only for single or multiple discrete seizures, mydriasis and clinically significant responses (a predetermined subset of CNS and cardiopulmonary clinical effects). Meaningful triage thresholds for citalopram could not be determined due to the low frequency of significant clinical effects.
Children develop minimal toxicity with SSRI ingestions. Seizures and ECG changes, while uncommon, occur more frequently with citalopram. Doses associated with significant outcomes suggest that the triage guideline for citalopram does not need to be modified.
Prolongation of the corrected QT interval (QTc) on the electrocardiography is an important clinical condition because it increases the risk of torsade de pointes, a medical emergency that can cause sudden cardiac death. QTc prolongation can be induced by many drugs, including antipsychotics and tricyclic antidepressants (TCAs). Compared with TCAs, use of selective serotonin reuptake inhibitors (SSRIs) was less likely to cause severe cardiac adverse effects. Escitalopram, one of the SSRIs, has shown significant antidepressant efficacy and well tolerability. Here, we present one female patient showing QTc prolongation induced by low-dose (5 mg/day) treatment of escitalopram for 2 days. The QTc returned to normal soon after discontinuation of escitalopram. Clinicians should be cautious about cardiac effects when using a SSRI, even in a low dose.
Many psychotropic drugs can delay cardiac repolarization and thereby prolong the rate-corrected QT interval (QTc). A prolonged QTc often arouses concern in clinical practice, as it can be followed, in rare cases, by the life-threatening polymorphic ventricular tachyarrhythmia called torsade de pointes (TdP).
We searched PubMed for pertinent literature on the risk of QTc prolongation and/or TdP associated with commonly used psychotropic drugs.
Thioridazine and ziprasidone confer the highest risk of QTc prolongation and/or TdP. There is also a clinically significant risk associated with haloperidol given intravenously in high doses. TdP has been reported in a few cases in association with the use of newer antipsychotic drugs (mainly quetiapine and amisulpride), most of the tri- and tetracyclic antidepressants, and the selective monoamine reuptake inhibitors citalopram, fluoxetine, paroxetine, and venlafaxine. As a rule, however, QTc prolongation and/or TdP occur only in the presence of multiple additional risk factors, such as age over 65 years, pre-existing cardiovascular disease, bradycardia, female sex, hypokalemia, hypomagnesemia, a supratherapeutic or toxic serum concentration, or the simultaneous administration of other drugs that delay repolarization or interfere with drug metabolism.
Before prescribing a psychotropic drug, the physician should carefully assess its risks and benefits to avoid this type of adverse reaction, particularly when additional risk factors are present. The ECG and electrolytes should be regularly monitored in patients taking psychotropic drugs.
Selective serotonin reuptake inhibitors are widely prescribed drugs without recognized cardiovascular risk. We report the case of a 54-year-old patient who developed QTc interval prolongation, followed by ventricular fibrillation episodes, 10 hours after admission to the ICU, in the setting of a citalopram overdose. Citalopram plasma values dropped from 5.88 to 0.34 mg/L at 9 days postadmission. The patient was treated by oral activated charcoal, and final outcome was favorable.
Long QT syndrome (LQTS) is a disorder of myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG). This disorder is associated with an increased risk of torsade de pointes (TdP). We report a case of TdP induced by citalopram, a selective serotonin reuptake inhibitor (SSRI), taken in conjunction with amiodarone.
A 65-year-old man with recently diagnosed urinary tract infection treated with ciprofloxacin (Cipro) presented to our institution with recurrent seizure-like activity. His rhythm revealed torsade de pointes, which required defibrillation. Subsequent electrocardiogram revealed severely prolonged QT interval, which near-completely resolved 7 days later off Cipro. This case highlights a rare but potentially fatal side effect of quinolone antibiotics, especially in combination with other QT-prolonging medications. Review of the literature with regard to prevalence, mechanism, and assessment and treatment of this potentially fatal incidence is provided.
In 1966, Francois Dessertenne described a specific electrocardiographic form of polymorphic ventricular tachycardia, which he termed “torsades de pointes” (TdP).w1 w2 The word “torsades” refers to an ornamental motif imitating twisted hairs or threads as seen on classical architectural columns, and “pointes” referred to points or peaks.w1 w2 In the seminal article, Dessertenne made no attempt to suggest the mechanism of TdP and, until recently, there has been considerable conjecture as to the pathophysiology of this arrhythmia.
Since the original work by Dessertenne, it has been well recognised that many conditions may cause prolonged or abnormal repolarisation (that is, QT interval prolongation and/or abnormal T or T/U wave morphology), which is associated with TdP. If TdP is rapid or prolonged, it can lead to ventricular fibrillation and sudden cardiac death (fig 1). Essentially, TdP may be caused by either congenital or acquired long QT syndrome (LQTS). In recent years, there has been considerable renewed interest in the assessment and understanding of ventricular repolarisation and TdP. There are several reasons for this. Firstly, the cloning of cardiac ion channels has improved the understanding of the role of ionic channels in mediating cardiac repolarisation, the pathophysiological mechanism of LQTS (congenital and acquired forms), and the pathogenesis of TdP. Secondly, modern molecular techniques have unravelled the mutations in genes encoding cardiac ion channels that cause long QT syndrome, although the genetic defects in about 50% of patients are still unknown. Thirdly, there has been considerable enthusiasm for the development and use of class III antiarrhythmic drugs, which prolong repolarisation and cardiac refractoriness. Unfortunately, drugs that alter repolarisation have now been recognised to increase the propensity for TdP. Finally, an increasing number of drugs, especially non-cardiac drugs, have been recognised to delay cardiac repolarisation and to share the ability with class III …
Polymorphic ventricular tachycardia is an uncommon arrhythmia with multiple causes. Classification and management are based on the QT interval. Torsades de pointes denotes polymorphic ventricular tachycardia in the setting of a prolonged QT interval and usually is iatrogenic in origin, though the congenital long QT syndrome is becoming recognized more frequently. Therapy of polymorphic ventricular tachycardia focuses on the establishment of hemodynamic stability, the removal and/or correction of precipitants,and the acute and chronic inhibition of subsequent episodes. Long-term management must be tailored to the individual and the underlying causes, and should be performed by an experienced cardiac electrophysiologist.
PMVT is an uncommon arrhythmia with multiple causes. Classification and management are based on the Q-T interval. Torsades de pointes denotes PMVT in the setting of a prolonged Q-T interval and usually is iatrogenic in origin, although congenital LQTS is being recognized more frequently. Therapy of PMVT focuses on the establishment of hemodynamic stability, the removal or correction of precipitants, and the acute and long-term inhibition of subsequent episodes. Evaluation of these patients should include a thorough history and physical examination and an assessment for underlying heart disease and known [figure: see text] eliciting factors. Long-term management must be tailored to the individual and the underlying cause and should be conducted by an experienced cardiac electrophysiologist.
Torsade de pointes ventricular tachyarrhythmia in the long QT syndrome is a prime example of how molecular biology, ion channel, and cellular and organ physiology, coupled with clinical observations, promise to be the future paradigm for advancement of medical knowledge. Both the congenital and the acquired long QT syndrome are caused by abnormalities (intrinsic, acquired, or both) of the ionic currents underlying ventricular repolarization. In this review, the continually unraveling molecular biology of congenital long QT syndrome is discussed. The various pharmacologic agents associated with the acquired long QT syndrome are listed. Although it is difficult to predict which patients are at risk for torsade de pointes, careful assessment of the risk to benefit ratio is important before prescribing drugs known to cause QT prolongation. The in vivo electrophysiologic mechanism of torsade de pointes in the long QT syndrome is described, using as a paradigm the anthopleurin-A canine model, a surrogate for LQT3. The characteristic association of torsade de pointes with T-wave alternans and short-long cardiac sequences is discussed, with emphasis on electrophysiologic mechanisms. Finally, the expanding knowledge of genetic mutations other than long QT syndrome associated with polymorphic ventricular tachyarrhythmia is emphasized.
Contempo Updates Section Editor: Sarah Pressman
Lovinger, MD, Fishbein Fellow.The long QT syndrome (LQTS) was first described in 1957 in a family
in which several children with congenital bilateral neural deafness and QT
prolongation on electrocardiogram (ECG) experienced recurrent syncope and
sudden death, with a family pattern that suggested autosomal recessive inheritance
(Jervell and Lange-Nielsen syndrome).1 A similar
and much more common familial disorder with QT prolongation but without deafness
was described a few years later, with family patterns that suggested autosomal
dominant inheritance (Romano-Ward syndrome). These reports highlighted the
familial nature of this QT prolongation disorder, and subsequent studies identified
malignant ventricular arrhythmias as the cause of syncope and sudden death
in patients with LQTS. The molecular-genetic basis of LQTS was discovered
in the 1990s and, currently, mutations have been identified in 7 LQTS genes
(Table 1).
In 1966, Francois Dessertenne described a specific electrocardiographic form of polymorphic ventricular tachycardia, which he termed "torsades de pointes" (TdP).w1w2 The word "torsades" refers to an ornamental motif imitating twisted hairs or threads as seen on classical architectural columns, and "pointes" referred to points or peaks.w1 w2 In the seminal article, Dessertenne made no attempt to suggest the mechanism of TdP and, until recently, there has been considerable conjecture as to the pathophysiology of this arrhythmia.
The single most common cause of the withdrawal or restriction of the use of marketed drugs has been QT-interval prolongation associated with polymorphic ventricular tachycardia, or torsade de pointes, a condition that can be fatal. This review summarizes the current knowledge about molecular and clinical predictors of drug-induced QT-interval prolongation and torsade de pointes and discusses how new molecular predictors of drug action might be incorporated into drug-development programs and clinical practice. A general approach to drugs suspected of causing this problem is presented.