In the January issue of the American Journal of Psychiatry two editorials have been published that deal again with the cardiac safety of citalopram. I have posted a contribution to the discussion last year. In my post from May 4th, 2013, I had discussed the study by Zivin et al. (2013), which had also been published in the American Journal of Psychiatry. The first of the two published editorials represents a discussion of the study by Zivin et al. by employees of the American Food and Drug Administration (FDA) (Bird et al., Am J Psychiatry 2014; 171: 17-19). In 2011 the FDA had published a warning on the QTc interval prolongation associated with citalopram and escitalopram, which the German authorities followed soon thereafter. The second editorial in turn is a reply of Zivin et al. (Zivin et al., Am J Psychiatry 2014; 171: 20-22) to Bird et al.
First of all I would like to refer to my discussion of the study by Zivin et al. (2013). Bird et al. (2014) are now stating under the title “Cardiac Safety Concerns Remain for Citalopram at Dosages Above 40 mg/Day” that the warning of citalopram doses above 40 mg daily is still justified. The reason for the warning is that the dosage of 60 mg citalopram resulted in a mean prolongation of the QTc interval of 18.5 ms. Although the authors acknowledge that it is not clear what degree of prolongation is a matter of concern, they assume that a prolongation of the QTc interval of more than 15 ms is associated with an increased risk of torsades de pointes. In addition, they point out that there is no justification for doses above 40 mg/day, as citalopram in clinical phase III trials in doses of 60 mg/day was not more effective than at doses of 40 mg/day.
Bird et al. further argue that even large observational studies (Zivin et al had based their study on the analysis of about 600,000 patient data) were not able to detect drug-induced torsades de pointes. None of eight observational studies had shown an increased risk of torsades de pointes for terfenadine or cisapride. However, both compounds were removed from the market because of exactly this risk. They claim that torsades de pointes are so rare that an increased risk can only be identified by case reports. The authors summarize their position as follows: “Clinical trial data, case reports, and studies in animals provide clear evidence for dose-dependent QT prolongation with citalopram. The nearly 20-ms mean effect (18.5 ms) on QT observed at the 60 mg/day dosage represents a significant concern, especially since this dosage was not more effective than 40 mg/day in clinical trials. The observational study by Zivin et al. does not mitigate the concern that led to the FDA’s recommendation to avoid the 60 mg/day dosage”.
In their reply under the title “Safety of high-dosage citalopram” Zivin et al. point out that other large studies also detected only a moderate risk for prolongation of the QT interval under citalopram (and also for other antidepressants such as amitriptyline). The data on which the FDA warning is based are still not published in a peer-review process. In addition, it is unclear in how many of the subjects of the two FDA studies a QT interval of longer than 500 ms was observed. On the other hand, the authors also admit that their data could be distorted by various forms of bias. For example, patients with increased cardiac risk might have been treated with lower doses of citalopram from the beginning. Torsades de pointes are the most common reason for FDA warnings, but for only 10 of 140 drugs with a known risk of Torsade de pointes an FDA warning was published. Thus, Zivin et al. claim that the policy of the FDA is inconsistent in terms of management and weighting the benefits and risks of a drug. Zivin et al. come to the conclusion: “Ultimately, it is up to clinicians and their patients to weigh these potential risks with the potential benefits. Clearly, there is a perceived clinical benefit to citalopram dosages above 40 mg/day; 12% of prescriptions in our study exceeded this threshold. Even if a randomized controlled trial did not find greater efficacy for 60 mg compared with 40 mg of citalopram, randomized controlled trials are limited in their generalizability to real-world patients and practices”.
On February 6th, 2012, the German DGPPN under my auspices published an opinion (only in German language) on the warnings of citalopram and escitalopram that were issued by the German authorities. In my opinion, the publication of the two current editorials do not change the assessment published therein.
This post is also available in: German