Leo Sher, M.D.

The U.S. Food and Drug Administration (FDA) has informed healthcare professionals and patients that the antidepressant Celexa (citalopram hydrobromide; also marketed as generics) should no longer be used at doses greater than 40 mg per day because it can cause abnormal changes in the electrical activity of the heart. Studies did not show a benefit in the treatment of depression at doses higher than 40 mg per day.  Previously, the citalopram drug label stated that certain patients may require a dose of 60 mg per day. 

FDA also suggest that 20 mg per day is the maximum recommended dose for patients with hepatic impairment, who are greater than 60 years of age, who are CYP 2C19 poor metabolizers, or who are taking concomitant cimetidine (Tagamet®), because these factors lead to increased blood levels of citalopram, increasing the risk of QT interval prolongation and Torsades de Pointes.

Torsades de Pointes is a polymorphic ventricular tachycardia associated with a fall in arterial blood pressure, which can result in syncope. Torsades de Pointes can lead to ventricular fibrillation and sudden death. Torsades de Pointes is associated with long QT syndrome.

The citalopram drug label has been revised to include the new drug dosage and usage recommendations, as well as information about the potential for QT interval prolongation and Torsades de Pointes.

FDA has received post-marketing reports of QT interval prolongation and Torsades de Pointes associated with Celexa and its generic equivalents. In addition, FDA has evaluated the results of a thorough QT study assessing the effects of 20-mg and 60-mg doses of citalopram on the QT interval in adults. Compared to placebo, maximum mean prolongations in the individually corrected QT intervals were 8.5 and 18.5 milliseconds (ms) for 20 mg and 60 mg citalopram, respectively. For 40 mg citalopram, prolongation of the corrected QT interval was estimated to be 12.6 ms. 

FDA states that patients with congestive heart failure, bradyarrhythmias, or predisposition to hypokalemia or hypomagnesemia because of concomitant illness or drugs, are at higher risk of developing Torsades de Pointes. Hypokalemia and hypomagnesemia should be corrected before administering citalopram. It has been recommended to consider more frequent electrocardiogram (ECG) monitoring in patients with congestive heart failure, bradyarrhythmias, or patients on concomitant medications that prolong the QT interval.

It is of interest to note that early preclinical studies in cats with citalopram, showed tricyclic antidepressant-like effects on the heart at high doses (2), and the development of citalopram was delayed by reports of cardiotoxicity in dogs, eventually attributed to a species-specific metabolite not found in humans (3).

About 3 years ago, a research group from Sweden analyzed spontaneously reported cases of Torsades de Pointes in Sweden and investigated if this adverse drug reaction was labeled in the summary of product characteristics for the drugs implicated (4). The authors found that although citalopram was the third most common suspected drug in the reports, Torsades de Pointes was not listed in the summary of product characteristics.

In 2008, The International Journal of Cardiology published the case report, “Citalopram induced torsade de pointes, a rare life threatening side effect” (5). The authors from a hospital in Rochester, Minnesota, reported that serial ECGs indicated normalization of the QT interval after citalopram was discontinued.

References

1. U.S. Food and Drug Administration. FDA Drug Safety Communication: Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide). http://www.fda.gov/Drugs/DrugSafety/ucm269086.htm  Accessed August 24, 2011.
2. Boeck V, Jorgensen A, Fredricson Overo K. Comparative animal studies on cardiovascular toxicity of tri- and tetracyclic antidepressants and citalopram; relation to drug plasma levels. Psychopharmacology (Berl) 1984; 82: 2 75-81.
3. Pacher P, Kecskemeti V. Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns? Curr Pharm Des 2004;10(20):2463-75.
4. Aström-Lilja C, Odeberg JM, Ekman E, Hägg S. Drug-induced torsades de pointes: a review of the Swedish pharmacovigilance database. Pharmacoepidemiol Drug Saf 2008;17(6):587-92.
5. Kanjanauthai S, Kanluen T, Chareonthaitawee P. Citalopram induced torsade de pointes, a rare life threatening side effect. Int J Cardiol 2008;131(1):e33-4.