Slight risk of QT-interval prolongation found with two antidepressants

Deborah Brauser

January 30, 2013

Boston, MA - Patients who receive high doses of the antidepressants citalopram or escitalopram could potentially develop QT-interval prolongation, a marker of a slight increased risk for ventricular arrhythmia and sudden death, new research suggests[1].

Investigators examined >38 000 electronic medical records and found a "slight but significant" association between QT prolongation and prescriptions of those two antidepressants. Other modern antidepressants, including fluoxetine, paroxetine, and sertraline, showed no QT-interval prolonging effect, whereas bupropion was actually associated with shortening of the QT interval.

In 2011, the US Food and Drug Administration (FDA) issued a warning that higher doses of citalopram were associated with QT-interval lengthening. "Our findings support the FDA's warning, so that wasn't necessarily a surprise," principal investigator Dr Roy H Perlis (Massachusetts General Hospital, Boston) said in an interview.

"It was interesting to find some effect on QT also with escitalopram, although it was probably less than with citalopram. And as it turned out, the effect was very different for other antidepressants. That should give people some reassurance," he said. Perlis added that the findings should not cause patients to stop taking either citalopram or escitalopram if already prescribed.

"The take-home message is that most of the newer antidepressants are very safe from a heart-rhythm perspective. I worry more about people stopping their antidepressants unnecessarily than about the QT-prolongation risks."

The study was published online January 29, 2013 in BMJ.

FDA guidance "minimal"

The initial FDA warning stated that doses of citalopram >40 mg/day should no longer be prescribed. In March 2012, the warning was revised to say that 20 mg/day should be the maximum dose for patients older than 60 years and for anyone taking a cytochrome P450 2C19 inhibitor.

However, Perlis stated that the warnings "gave us minimal clinical guidance"—and left both patients and clinicians with more questions than answers. "The impetus for this study came directly from the phone calls we received from colleagues and from patients taking citalopram asking what they should do. We realized that to get a satisfying answer, we needed to get more data," he said.

Dose-dependent link

The researchers examined electronic health records for 38 397 adult patients (mean age 58 years; 60% women). Of these, 80% were white, 7.8% were Hispanic, and 7.2% were black.

All patients had undergone an ECG 14 to 90 days after receiving a prescription for one of 11 antidepressant medications or for methadone between February 1990 and August 2011. Methadone was included in the analysis because it is a known contributor to QT prolongation.

A significantly longer-than-normal QT interval was observed in patients receiving the selective serotonin-reuptake inhibitors (SSRIs) citalopram (p<0.01) and escitalopram (p<0.001), the tricyclic antidepressant amitriptyline (p<0.001), and methadone (p<0.001).

"This effect increased at higher doses, suggesting a dose-response association," said Perlis.

"Nearly one in five patients treated with these antidepressants who underwent ECG had QT intervals that would be considered abnormal," write the investigators, adding that the clinical significance of this is not yet known.

Benefits outweigh risk

A significantly shorter QT interval was found for those receiving bupropion, even at higher doses (p<0.05). No effect on QT interval was shown for any dose of fluoxetine, paroxetine, sertraline, duloxetine, mirtazapine, nortriptyline, or venlafaxine.

"For patients starting a new antidepressant who have other risk factors for arrhythmias, a drug other than citalopram would probably be a wise choice. But for those already taking lower doses, the QT-prolongation effects seem to be modest," said Perlis in a release.

Although an increased QT interval is a risk factor for abnormal heart rhythms, these abnormal rhythms are extremely rare, he noted. "So for the vast majority of patients, the potential benefits in treating depression or anxiety far exceed the risk."

The study was funded by grants from the National Institutes of Health/National Library of Medicine and from the National Institute of Mental Health. Perlis has received consulting fees from or served on scientific advisory boards for Proteus Biomedical, Pamlab, Genomind, and RIDventures and has received research grant support from Proteus Biomedical and royalties from Concordant Rater Systems.Disclosures for the coauthors are listed in the paper.

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