Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.
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 August 2011, the U.S. Food and Drug Administration (FDA) issued a drug safety communication that the antidepressant drug citalopram (Celexa®) should not be used at dosages greater than 40 mg per day (or greater than 20 mg per day for patients 60 and older) because higher doses have been associated with abnormal heart rhythms (FDA, 2011). Last month, I critically evaluated the basis for this warning. In this article, I will review additional studies pertinent to evaluating the potential cardiotoxicity of citalopram.
Citalopram in Clinical Studies of Patients with Cardiac Disease
In the Sequenced Treatment Alternative to Relieve Depression (STAR*D) study, 2,876 patients received citalopram 20 to 60 mg per day for up to 14 weeks in the first level (Trivedi et al., 2006). More than half of those participants took more than 40 mg per day. Because STAR*D was intended to be a “real-world” clinical trial, approximately 40% of participants were recruited from primary care medical sites, and comorbid general medical conditions (including cardiac) and concurrent medications (including cardiac) did not exclude patients from entering the study. The remaining 60% of participants were recruited from psychiatric clinics. The age range was 18 to 75, and 25% were older than 50. Participants had a wide variety of comorbid general medical conditions, but 8.4% in the medical settings and 4.8% in the psychiatric settings had heart conditions. Only 8% of participants discontinued citalopram because of medication intolerance. Three died (1 from a medical setting, 2 from psychiatric settings). Among the participants hospitalized for nonpsychiatric reasons, 22 came from medical settings (2%) and 36 from psychiatric settings (2%).
Although electrocardiogram (ECG) monitoring was not conducted, there was no clear “cardiac” signal based on adverse clinical events from STAR*D. Even if all 3 participant deaths and all 58 medical hospitalizations could be attributed to citalopram-associated cardiotoxicity (which was not the case), these event rates are so low that they would be difficult to distinguish from the expected background mortality rates and hospitalization rates for depressed patients ages 18 to 75 who are treated in these primary care medical and psychiatric settings.
In the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial, depressed participants with pre-existing coronary artery disease were randomized to receive psychotherapy plus placebo, citalopram plus clinical management, psychotherapy plus citalopram, or clinical management plus placebo for 12 weeks (Lésperance et al., 2007). Citalopram doses were 20 to 40 mg per day. The mean age of participants was approximately 60. All took a variety of concomitant cardiovascular medications. There were no differences between citalopram and placebo in any blood pressure, heart rate, or ECG measures (including QTc interval). Compared with placebo, the use of citalopram was not associated with any serious adverse cardiovascular events.
In an open-label study of 110 depressed adults (older than age 80) taking citalopram 20 to 40 mg per day or sertraline (Zoloft®) 50 to 100 mg per day, Santangelo et al. (2009) monitored these participants for sudden cardiac deaths or other cardiovascular events for 1 year. Overall, the researchers observed a 75% reduction of cardiovascular events after 4 months, an 83% reduction after 6 months, and a 60% reduction after 12 months. There were no apparent differences between the two drugs. No ECG data were reported.
Therapeutic Drug Monitoring Studies with Citalopram
As described in last month’s article, “citalopram is metabolized primarily by the cytochrome P-450 (CYP) hepatic enzymes CYP3A4 and CYP2C19, with a smaller contribution from CYP2D6. The major metabolite is demethylcitalopram (DCT), which is subsequently metabolized by CYP2D6 to the minor metabolite didemethylcitalopram (DDCT)” (Howland, 2011, p. 14). High DDCT concentrations have been associated with QT interval prolongation in beagle dogs (Howland, 2011).
In a therapeutic drug monitoring study, Le Bloc’h et al. (2003) determined the plasma concentrations of citalopram, DCT, and DDCT in 345 samples from 258 patients taking citalopram 10 to 360 mg per day. Among patients taking 60 mg per day or less, 160 samples were analyzed. The remaining 185 samples were analyzed from patients taking 61 to 120 mg per day (93 samples), 121 to 200 mg per day (70 samples), 201 to 280 mg per day (18 samples), and 281 to 360 mg per day (4 samples). Patients were apparently taking such high doses because of treatment nonresponse. No ECG data or adverse clinical events were reported in this study. There was direct linear correlation between oral citalopram dose and plasma citalopram concentration. The highest mean citalopram concentration (888 ng/mL) was found in the 281-to-360-mg-per-day group. The highest single sample citalopram concentration (1814 ng/mL) was obtained from a patient taking 360 mg per day. There was only a small correlation between oral citalopram dose and plasma DDCT concentration. The highest mean DDCT concentration (37 ng/mL) was found in the group taking 201 to 281 mg per day. The highest single sample DDCT concentration (100 ng/mL) was found in a patient taking 280 mg per day.
According to information described in the Celexa product package insert (Forest Pharmaceuticals, Inc., 2011), DDCT plasma concentrations obtained from 2,020 citalopram-treated patients (taking unknown doses) revealed that DDCT levels rarely exceeded 21 ng/mL. Moreover, the highest measured DDCT concentration in human overdose was 42 ng/mL.
Variations in a particular gene are referred to as genetic polymorphisms. Genetic polymorphisms occur with each of the CYP genes, affecting the activity of the enzyme, which can influence how a person metabolizes certain drugs. The metabolic activity of CYP enzymes 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 metabolizers have higher serum concentrations of some drugs. The AmpliChip® CYP450 Test (Roche Diagnostics, http://www.roche.com) is a commercially available product that analyzes genetic polymorphisms of CYP2D6 and CYP2C19. Using this blood test, CYP2D6 metabolic activity is characterized as poor, intermediate, extensive, or ultra-rapid, and CYP2C19 activity as poor or extensive. The prevalence of CYP2D6 ultra-rapid metabolizers is less than 2% in the United States (de Leon, 2007). In theory, patients who are CYP2D6 ultra-rapid metabolizers could generate higher serum concentrations of the citalopram metabolite DDCT (Kingbäck, Carlsson, Ahlner, Bengtsson, & Kugelberg, 2011) and they might be at higher risk for citalopram-associated cardiotoxicity. By contrast, concurrent use of drugs that inhibit CYP2D6 enzyme activity would be expected to have a “preventive” effect on the generation of DDCT.
Because the beagle dogs study (described in Forest Pharmaceuticals, Inc., 2011) found that QT interval prolongation was associated with DDCT concentrations greater than 250 ng/mL, the Le Bloc’h et al. (2003) therapeutic drug monitoring study data and the Celexa product package insert data (total of 2,278 patients from both studies) suggest that routine or even high oral doses of citalopram are unlikely to result in cardiotoxic concentrations of the DDCT metabolite.
Depression and Cardiovascular Risk
Interpreting the potential cardiotoxic effects of antidepressant drugs should also take into consideration the inherent effect of depression on cardiovascular function. Many studies have shown that depression is an independent risk factor for the development of cardiovascular disease, and that comorbid depression increases the morbidity and mortality of patients with pre-existing heart disease (Sher, Lolak, & Maldonado, 2010). Depression also contributes to the risk of developing cardiac arrhythmias (Brown, Barton, & Lambert, 2009). Minoretti et al. (2006) found that an increased QTc interval was significantly associated with the depression-related personality trait of neuroticism in healthy unmedicated men. Hintsa et al. (2009) found that depressive symptoms were significantly associated with cardiac arrhythmic events in patients with the congenital long QT syndrome.
Clinical Considerations with Citalopram Dosing
There are clinically justifiable reasons for using citalopram in dosages greater than 40 mg per day for depression, obsessive-compulsive disorder, and probably other anxiety disorders. The FDA statement that studies have not shown a benefit in the treatment of depression at doses higher than 40 mg per day is misleading. This statement is based on short-term, fixed-dose studies comparing outcomes in patients randomized to fixed doses of 10, 20, 40, or 60 mg per day (Montgomery, 1995). Although the average response rate for the 40-mg-per-day group and the 60-mg-per-day group is similar in a fixed dose study, this finding does not prove that a subgroup of patients not responding adequately to a particular dose will not respond better to a subsequent dose increase. Fixed-dose studies simply are not designed to optimize treatment outcomes, especially for individual patients. Limiting the use of a medication to suboptimal doses will not necessarily result in safer treatment, but it will increase the likelihood of a suboptimal clinical response. Indeed, if one is concerned about the cardiotoxicity of citalopram and therefore uses a less-than-optimal dose, there is a risk that undertreating depression will result in depression complications, including suicide attempts by overdose. Using lower doses of citalopram, or avoiding the drug entirely, because of cardiotoxicity concerns will not ensure patient safety. Patients may be harmed or even die by overdosing on many other prescription or nonprescription medications.
For prescribers who are absolutely risk averse and have a zero-tolerance threshold for potential adverse cardiac events, the ECG could be monitored in patients taking higher citalopram doses. If a baseline ECG has not been done, however, it is not possible to know whether it is affecting the QTc. Unless the QTc is near or above a 450 to 500 msec threshold, one should not be overly concerned. Clinicians who are very concerned about this issue with the use of citalopram should familiarize themselves with the potential cardiac effects of many other psychotropic and nonpsychotropic drugs patients are taking. These QTc findings are not unique to citalopram. When prescribing psychotropic medications (not just citalopram), it is prudent to be aware of underlying medical conditions that might have cardiac effects and to know all of the prescription and nonprescription drugs being used concurrently.
Based on the studies reviewed in this and in last month’s article, the citalopram dose limitations described in the FDA safety announcement do not have strong clinical justification. The totality of data from a variety of studies provide no evidence that the routine clinical use of citalopram in doses of 60 mg per day would be less safe than using doses of 40 mg per day or less. The available data do not provide evidence that high-dose citalopram (i.e., doses greater than 60 mg per day) are necessarily riskier than lower doses. There is no clear evidence that citalopram has greater clinically relevant cardiotoxicity compared with other antidepressant drugs. Although citalopram overdose is not entirely “cardiac safe,” this risk is not meaningfully different than that of other new-generation antidepressant drugs. Nurses should be able to discuss these issues with patients who have questions or concerns about the use of citalopram.
- Brown, A.D., Barton, D.A. & Lambert, G.W. (2009). Cardiovascular abnormalities in patients with major depressive disorder: Autonomic mechanisms and implications for treatment. CNS Drugs, 23, 583–602. doi:10.2165/00023210-200923070-00004 [CrossRef]
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- Forest Pharmaceuticals, Inc. (2011). Celexa® (citalopram hydrobromide) tablets/oral solution. Retrieved from http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020822s038s040,021046s016s017lbl.pdf
- Hintsa, T., Keltikangas-Järvinen, L., Puttonen, S., Ravaja, N., Toivonen, L., Kontula, K. & Swan, H. (2009). Depressive symptoms in the congenital long QT syndrome. Annals of Medicine, 41, 516–521. doi:10.1080/07853890903037254 [CrossRef]
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- Kingbäck, M., Carlsson, B., Ahlner, J., Bengtsson, F. & Kugelberg, F.C. (2011). Cytochrome P450-dependent disposition of the enantiomers of citalopram and its metabolites: In vivo studies in Sprague-Dawley and Dark Agouti rats. Chirality, 23, 172–177. doi:10.1002/chir.20901 [CrossRef]
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- Minoretti, P., Politi, P., Martinelli, V., Emanuele, E., Bertona, M., Falcone, C. & Geroldi, D. (2006). QT interval duration in apparently healthy men is associated with depression-related personality trait neuroticism. Journal of Psychosomatic Research, 61, 19–23. doi:10.1016/j.jpsychores.2006.01.001 [CrossRef]
- Montgomery, S.A. (1995). Selecting the optimum therapeutic dose of serotonin reuptake inhibitors: Studies with citalopram. International Clinical Psychopharmacology, 10(Suppl. 1), 23–27. doi:10.1097/00004850-199503001-00005 [CrossRef]
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- U.S. Food and Drug Administration. (2011). FDA drug safety communication: Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide). Retrieved from http://www.fda.gov/Drugs/DrugSafety/ucm269086.htm