Cardiac Safety of Citalopram
Abstract & Commentary
Source: Rasmussen SL, et al. Cardiac safety of citalopram: Prospective trials and retrospective analyses. J Clin Psychopharmacol 1999;19:407-415.
Citalopram (celexa) is the newest available antidepressant in the class of selective serotonin reuptake inhibitors (SSRIs). While SSRIs are typically regarded as benign in terms of adverse cardiovascular effects, there has been some research in beagle dogs that suggests that a metabolite of citalopram, didemethylcitalopram (DDCT), may cause prolongation of the QT interval.
The current paper reports findings of a randomized, double-blind, placebo-controlled study of healthy volunteers (n = 23) designed to assess QTc interval changes during treatment with placebo or citalopram, and the correlation of such changes to plasma drug levels. The subjects, aged 21-41 years, had baseline ECGs performed, received placebo for three days as a run-in, and were then randomized to receive either placebo or citalopram 60 mg/d (maximum recommended daily dose) for four weeks. Repeat ECGs were performed several times during the placebo run-in period, at steady-state, and at the end of the treatment period. There were no statistically significant differences between the two arms at baseline, during run-in, or at steady-state. Further, there was no correlation between QTc intervals and serum concentrations of DDCT. Consistent with previous reports that beagle dogs have higher relative concentrations of DDCT due to species-specific differences in metabolism, DDCT was present in very low concentration in the healthy human subjects.
In addition to the study of healthy volunteers, the current paper reported the ECG findings of three randomized, double-blind, placebo- or active-controlled, fixed-dose trials in adult and elderly depressed or demented patients (n = 1460) in addition to more than 6000 ECGs performed in 1789 citalopram-treated patients collected from all clinical trials conducted from 1978 through 1996. In both the prospective and retrospective analyses, there were no significant effects on QTc intervals, indicating that citalopram has no effect on cardiac repolarization. Citalopram did cause a reduction in heart rate (~ £ 8 beats/min), which is consistent with some reports of fluoxetine-associated bradycardia.
COMMENT BY MICHAEL F. BARBER, Pharmd
The importance of screening and treating depression in patients with cardiovascular disease has been emphasized previously. While it is apparent that SSRIs represent a much more favorable class of antidepressants compared to tricyclic antidepressants (TCAs) in terms of cardiac safety, the data on the magnitude of their effects on the QT interval have been somewhat sparse. Since there had been reports of citalopram-associated prolongation of the QT interval in beagle dogs, there was clearly a necessity for an investigation of such effects in humans. The current report suggests that citalopram is not likely to prolong the QT interval in humans. However, the results should be taken cautiously since a complete lack of QT effects cannot be ruled out in all patients. For instance, the data from the beagle dogs study seemed suggestive that animals that exhibit extensive metabolism of citalopram via CYP2D6 will achieve higher serum concentrations of DDCT, leading to QT prolongation. Since subjects in the current study were not phenotyped for CYP2D6, it is not clear whether humans who are extensive metabolizers of citalopram via CYP2D6 would display elevated concentrations of DDCT and may be at higher risk for QT prolongation. Further, since the patients in the trials were relatively free of cardiac disease, citalopram's safety for use in patients with cardiovascular disease has yet to be described. There has been at least one death reported in an overdose of citalopram; however, the exact cause of death was not established. Therefore, it would seem appropriate to use citalopram with caution in patients who are at high risk for developing arrhythmias due to QT prolongation (i.e., patients with prolonged QT at baseline, patients who are receiving medications known to prolong the QT interval such as quinidine, or patients with hypokalemia) until further data are available.
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