Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author has disclosed no potential conflicts of interest, financial or otherwise.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.
In response to my articles about the potential cardiac toxicity of citalopram (Celexa®) (Howland, 2011a, 2011b), I have received questions about escitalopram (Lexapro®), including the following correspondence from one reader, which I thought would be good to address in this month’s column:
I’ve been taking citalopram 60 mg for several years with no adverse effects. Although the 40-mg dose was effective, I’ve found the 60-mg dose to be better still. Thus, I am hesitant to switch doses based on weak data. One question I had concerned the active (S)-stereoisomer of citalopram, escitalopram. Specifically, would a 30-mg escitalopram dose produce less of the toxic breakdown product didemethylcitalopram (DDCT) than a 60-mg citalopram dose? From what I could tell, DDCT is produced by metabolized escitalopram, but it wasn’t clear if the breakdown products of both isoforms in citalopram contribute to producing toxic forms of DDCT. If so, then switching to escitalopram could be a means to circumvent these issues. Any comments on this would be greatly appreciated and would probably be of general interest to clinicians and patients.
Electrocardiogram Studies of Escitalopram
A potential effect of many psychotropic and nonpsychotropic drugs is to delay cardiac repolarization, which can be quantified by measuring the duration of the QT interval on an electrocardiogram (ECG) tracing. The measurement of the QT interval is adjusted according to the heart rate, and this is referred to as the corrected QT (QTc) interval. An abnormally prolonged QTc interval is associated with an increased risk of developing the ventricular tachyarrhythmia torsade de pointes that can result in sudden death. However, the definition of an “abnormal” QTc interval has not been precisely established, and various methods for measuring and correcting the QT interval have been used (Luo, Michler, Johnston, & Macfarlane, 2004).
According to unpublished data described in the Lexapro product package insert (Forest Pharmaceuticals, Inc., 2011), two ECG studies have been conducted. In one study, ECGs were analyzed from 625 participants taking escitalopram (unknown dose) and 527 taking placebo. Participants were classified as “outliers” according to specific criteria. The ECG outliers were defined as participants with QTc changes greater than 60 milliseconds (msec) from baseline or absolute QTc values greater than 500 msec post dose. Tachycardia outliers were defined as participants with heart rate increases to greater than 100 beats per minutes (bpm) along with a 25% change from baseline. Bradycardia outliers were defined as having heart rate decreases to less than 50 bpm, along with a 25% change from baseline. Fridericia’s formula (Luo et al., 2004) was used to calculate the QTc interval (referred to as the QTcF interval). Compared with 0.2% of placebo participants, none of the escitalopram participants had a QTcF interval greater than 500 msec or a QTcF interval prolongation greater than 60 msec. The incidence of tachycardia outliers was 0.2% in both groups. The incidence of bradycardia outliers was 0.5% for escitalopram and 0.2% for placebo.
In a second study, the QTcF interval was evaluated in a randomized, double-blind, placebo-controlled, active drug-controlled, escalating multiple-dose crossover study of 113 healthy non-depressed participants. The antibiotic agent moxifloxacin (Avelox®) 400 mg per day was used as the active control drug because it has been associated with QT interval prolongation. Participants received escitalopram 10 mg per day and 30 mg per day. Compared with placebo, the maximum mean QTcF interval prolongation was 4.5 msec for 10 mg per day and 10.7 msec for 30 mg per day. For 20 mg per day, QTcF interval prolongation was estimated to be 6.6 msec. No QTcF data were reported for moxifloxacin. The magnitude of the mean change in the QTcF interval (for 30 mg versus placebo) was small (10.7 msec), and its statistical significance was not reported. By comparison, the maximum mean QTc interval prolongation was 18.5 msec for a similar study of citalopram 60 mg per day. The threshold used by the U.S. Food and Drug Administration for clinical significance of the QTc interval is an absolute duration greater than or equal to 500 msec or a change from baseline greater than or equal to 60 msec. This study does not report whether any participants taking escitalopram or moxifloxacin exceeded either threshold.
Metabolism and Therapeutic Drug Monitoring Studies with Escitalopram and Citalopram
Citalopram is metabolized by the cytochrome P-450 (CYP) hepatic enzymes CYP3A4 and CYP2C19 to its major metabolite demethylcitalopram (DCT), which is subsequently metabolized by CYP2D6 to the minor metabolite DDCT (Herrlin et al., 2003). Unchanged citalopram is the predominant compound in plasma. Concentrations of DCT and DDCT are approximately one half and one tenth, respectively, than that of citalopram.
Citalopram is a racemic mixture of an S-enantiomer (escitalopram) and an R-enantiomer. Escitalopram is converted to its major metabolite S-DCT by CYP3A4 and CYP2C19 and then subsequently to the minor metabolite S-DDCT by CYP2D6 (Søgaard, Mengel, Rao, & Larsen, 2005). Unchanged escitalopram is the predominant compound in plasma and the concentration of S-DCT is approximately one third that of escitalopram, but the concentration of S-DDCT is not detectable in most participants. The therapeutic pharmacological activity of citalopram (serotonin reuptake inhibition) is mostly attributable to the S-enantiomer, and the R-enantiomer may competitively interfere with this effect. The metabolites do not appear to have any therapeutic pharmacological effects, but DDCT has been implicated in the potential adverse cardiac effects associated with citalopram. In the toxicology study described in the Lexapro product package insert (Forest Pharmaceuticals, Inc., 2011), 5 of 10 beagle dogs receiving oral citalopram died. A subsequent study in beagle dogs determined that intravenous racemic DDCT caused QT interval prolongation. This QT effect was associated with peak DDCT concentrations in the range of 810 to 3,250 nmol/L. I can find no studies that have investigated whether the QT prolongation effect is due to S-DDCT (or to R-DDCT).
In a therapeutic drug monitoring study, Reis, Cherma, Carlsson, and Bengtsson (2007) determined the concentrations of escitalopram, S-DCT, and S-DDCT in samples from 155 patients taking escitalopram 5 to 40 mg per day. No ECG data were reported. There was a significant linear correlation between the oral escitalopram dose and both the plasma escitalopram and S-DCT concentrations. There was not a significant correlation between escitalopram dose and S-DDCT concentration. The median S-DDCT concentration ranged from 3 to 10 nmol/L. The highest median S-DDCT concentration (10 nmol/L) was found in the 25-mg-per-day group. The highest maximum S-DDCT concentration (209 nmol/L) was obtained from a patient taking 15 mg per day.
Genetic polymorphisms can occur with each of the CYP genes, some of which can affect enzyme activity and influence how a person metabolizes certain drugs. The metabolic activity of the CYP2D6 enzyme can be categorized as ultra-rapid, extensive, intermediate, or poor. Poor metabolism is characterized by the absence of enzyme activity, whereas ultra-rapid metabolism is characterized by excessive enzyme activity. Extensive metabolism is considered to be mostly normal enzyme activity, and intermediate metabolism is considered to be slightly decreased enzyme activity. Patients who are poor or intermediate CYP2D6 metabolizers have higher serum concentrations of some drugs. The prevalence of CYP2D6 ultra-rapid metabolizers is less than 2% in the United States (de Leon, 2007). The metabolic activity of the CYP2C19 enzyme can be characterized as poor (the absence of enzyme activity) or extensive (mostly normal enzyme activity). The prevalence of CYP2C19 poor metabolizers is approximately 3% to 5% in Caucasians and 15% to 20% in Asians (Desta, Zhao, Shin, & Flockhart, 2002). Genetic polymorphisms of the CYP3A4 enzyme have been described, but they do not affect its metabolic activity. Patients who are CYP2D6 ultra-rapid metabolizers theoretically could generate higher serum concentrations of the escitalopram metabolite S-DDCT, resulting in a potentially higher risk for escitalopram-associated cardiotoxicity. Taking drugs that induce CYP2D6 activity also could generate increased S-DDCT concentrations. By contrast, concurrent use of drugs that inhibit CYP2D6 activity would result in reduced concentrations of S-DDCT. Taking drugs that induce CYP3A4 and CYP2C19 enzyme activity could increase S-DCT concentrations, but its conversion to S-DDCT would still be dependent on CYP2D6 enzyme activity.
Because of different study methods, comparing metabolite concentrations for citalopram 60 mg per day and for escitalopram 30 mg per day is problematic. In a therapeutic drug monitoring study, concentrations of citalopram, DCT, and DDCT were determined in 258 patients taking citalopram 10 to 360 mg per day (Le Bloc’h et al., 2003). For the 21- to 60-mg-per-day group, the median DDCT concentration was 16.6 nmol/L; for the 61- to 120-mg-per-day group, the DDCT concentration was 23.2 nmol/L. By comparison, Reis et al. (2007) determined that patients taking escitalopram 30 mg per day had a median S-DDCT concentration of 8 nmol/L. Because QT prolongation is associated with DDCT concentrations of 810 to 3,250 nmol/L, the Reis et al. (2007) data suggest that escitalopram doses up to 40 mg per day are unlikely to result in potentially cardiotoxic concentrations of the S-DDCT metabolite.
Post-Marketing Reports of Escitalopram-Associated Cardiotoxicity
In the published literature, a relatively small number of individual case reports of cardiac toxicity are associated with escitalopram (Tseng, Lee, Lin, & Lin, 2012). Approximately 500 cases of escitalopram overdoses (most including the ingestion of other drugs) are described in two published studies. van Gorp, Whyte, and Isbister (2009) described 78 cases of escitalopram overdoses in which 11 patients (14%) developed QTc prolongation. Hayes, Klein-Schwartz, Clark, Muller, and Miloradovich (2010) conducted a retrospective review of 421 escitalopram and 374 citalopram overdoses. There was no significant difference in the proportion of escitalopram patients having a prolonged QTc (1.7%) compared with citalopram (3.7%). No patients died, and there were no serious cardiac sequelae in either study.
Escitalopram in Clinical Studies of Older Patients
In an 8-week randomized, double-blind, placebo-controlled trial comparing escitalopram 10 mg per day and fluoxetine (Prozac®) 20 mg per day in 517 depressed patients ages 65 to 93, Kasper, de Swart, and Andersen (2005) reported no clinically relevant differences in ECG values within or between the treatment groups. During a 52-week extensive phase of this study, 223 patients continued to take escitalopram 10 to 20 mg per day (Kasper, Lemming, & de Swart, 2006). The mean change in the QTc interval was 0.0 msec. Four participants were reported to have had “high QTc intervals” during the study, but the actual intervals were not reported and these findings were not reported as adverse events related to treatment. A placebo-controlled study investigating the use of escitalopram in nondepressed patients with acute coronary syndrome has been initiated (Hansen, Hanash, Rasmussen, Hansen, & Birket-Smith, 2009).
Escitalopram has a small effect on the QTc interval. A prolonged QTc was seen in 2% to 14% of escitalopram overdose cases, without serious cardiac sequelae. The QTc effect is attributed to the minor metabolite racemic DDCT. Whether S-DDCT has this effect is not known. The equivalent dosage for escitalopram is half that of citalopram. Concentrations of S-DDCT are lower than DDCT. For a broad range of doses of each drug, the DDCT and S-DDCT concentrations are well below the QTc prolonging concentrations reported in dogs. Some readers might believe that escitalopram is “safer” than citalopram, but I think any difference is negligible. When cost is a consideration, generic citalopram is preferred over brand-name escitalopram by patients or insurance payers. Nurses should be able to counsel patients about the relative cardiac safety of escitalopram and citalopram.
- de Leon, J. (2007). The crucial role of the therapeutic window in understanding the clinical relevance of the poor versus the ultrarapid metabolizer phenotypes in subjects taking drugs metabolized by CYP2D6 and CYP2C19. Journal of Clinical Psychopharmacology, 27, 241–245. doi:10.1097/JCP.0b013e318058244d [CrossRef]
- Desta, Z., Zhao, X., Shin, J.G. & Flockhart, D.A. (2002). Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clinical Pharmacokinetics, 41, 913–958. doi:10.2165/00003088-200241120-00002 [CrossRef]
- Forest Pharmaceuticals, Inc. (2011). Lexapro product package insert. Retrieved from http://www.frx.com/pi/lexapro_pi.pdf
- Hansen, B.H., Hanash, J.A., Rasmussen, A., Hansen, J.F. & Birket-Smith, M. (2009). Rationale, design, and methodology of a double-blind, randomized, placebo-controlled study of escitalopram in prevention of Depression in Acute Coronary Syndrome (DECARD). Trials, 10. Retrieved from http://www.trialsjournal.com/content/10/1/20. doi:10.1186/1745-6215-10-20 [CrossRef]
- Hayes, B.D., Klein-Schwartz, W., Clark, R.F., Muller, A.A. & Miloradovich, J.E. (2010). Comparison of toxicity of acute overdoses with citalopram and escitalopram. Journal of Emergency Medicine, 39, 44–48. doi:10.1016/j.jemermed.2008.06.030 [CrossRef]
- Herrlin, K., Yasui-Furukori, N., Tybring, G., Widén, J., Gustafsson, L.L. & Bertilsson, L. (2003). Metabolism of citalopram enantiomers in CYP2C19/CYP2D6 phenotyped panels of healthy Swedes. British Journal of Clinical Pharmacology, 56, 415–421. doi:10.1046/j.1365-2125.2003.01874.x [CrossRef]
- Howland, R.H. (2011a). A critical evaluation of the cardiac toxicity of citalopram—Part 1. Journal of Psychosocial Nursing and Mental Health Services, 49(11), 13–16. doi:10.3928/02793695-20111011-01 [CrossRef]
- Howland, R.H. (2011b). A critical evaluation of the cardiac toxicity of citalopram—Part 2. Journal of Psychosocial Nursing and Mental Health Services, 49(12), 13–16. doi:10.3928/02793695-20111102-04 [CrossRef]
- Kasper, S., de Swart, H. & Andersen, H.F. (2005). Escitalopram in the treatment of depressed elderly patients. American Journal of Geriatric Psychiatry, 13, 884–891.
- Kasper, S., Lemming, O.M. & de Swart, H. (2006). Escitalopram in the long-term treatment of major depressive disorder in elderly patients. Neuropsychobiology, 54, 152–159. doi:10.1159/000098650 [CrossRef]
- Le Bloc’h, Y., Woggon, B., Weissenrieder, H., Brawand-Amey, M., Spagnoli, J., Eap, C.B. & Baumann, P. (2003). Routine therapeutic drug monitoring in patients treated with 10–360 mg/day citalopram. Therapeutic Drug Monitoring, 25, 600–608. doi:10.1097/00007691-200310000-00010 [CrossRef]
- Luo, S., Michler, K., Johnston, P. & Macfarlane, P.W. (2004). A comparison of commonly used QT correction formulae: The effect of heart rate on the QTc of normal ECGs. Journal of Electrocardiology, 37(Suppl.), 81–90. doi:10.1016/j.jelectrocard.2004.08.030 [CrossRef]
- Reis, M., Cherma, M.D., Carlsson, B. & Bengtsson, F. (2007). Therapeutic drug monitoring of escitalopram in an outpatient setting. Therapeutic Drug Monitoring, 29, 758–766. doi:10.1097/FTD.0b013e31815b3f62 [CrossRef]
- Søgaard, B., Mengel, H., Rao, N. & Larsen, F. (2005). The pharmacokinetics of escitalopram after oral and intravenous administration of single and multiple doses to healthy subjects. Journal of Clinical Pharmacology, 45, 1400–1406. doi:10.1177/0091270005280860 [CrossRef]
- Tseng, P.-T., Lee, Y., Lin, Y.-E. & Lin, P.-Y. (2012). Low-dose escitalopram for 2 days associated with corrected QT interval prolongation in a middle-aged woman: A case report and literature review. General Hospital Psychiatry, 34, 210.e13–210.e15. doi:10.1016/j.genhosppsych.2011.10.005 [CrossRef]
- van Gorp, F., Whyte, I.M. & Isbister, G.K. (2009). Clinical and ECG effects of escitalopram overdose. Annals of Emergency Medicine, 54, 404–408. doi:10.1016/j.annemergmed.2009.04.016 [CrossRef]