Some Antidepressants May Boost Arrhythmia Risk

Deborah Brauser

January 29, 2013

Patients who receive high doses of some, but not all, antidepressants may be at risk of developing prolongation of the QT interval, a marker for possible ventricular arrhythmia, new research suggests.

Investigators examined more than 38,000 electronic medical records and found a "slight but significant" association between QT prolongation and prescriptions of citalopram or escitalopram. Similar to previous research, a significant association was also found for amitriptyline and methadone.

Other antidepressants, including fluoxetine, paroxetine, and sertraline, showed no effect on QT interval, 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.

Dr. Roy Perlis

"Our findings support the FDA's warning, so that wasn't necessarily a surprise," principal investigator Roy H. Perlis, MD, director of the Center for Experimental Drugs and Diagnostics in the Department of Psychiatry at Massachusetts General Hospital in Boston and associate professor of psychiatry at Harvard Medical School, told Medscape Medical News.

"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.

Dr. 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 in the British Journal of Psychiatry (BMJ).

FDA Guidance "Minimal"

The QT interval is "the time from the beginning of electrical activation of the heart to the end of electrical relaxation," the investigators explain in a release.

"While the vast majority of individuals with QT prolongation have no heart rhythm abnormalities, it is a recognized risk factor for a rare but dangerous arrhythmia called torsades de pointes."

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

However, Dr. 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.

"Citalopram is one of the most prescribed antidepressants in the US and, frankly, around the world. The doses referred to by the FDA were not especially unusual in clinical practice, and there was no information about any of the other antidepressants. So all of this prompted us to see if we could see an effect in our records."

Dose-Dependent Link

The researchers examined electronic health records from Massachusetts General Hospital and partners for 38,397 adult patients (mean age, 58.3 years; 60% women). Of these, 80% were white, 7.8% were Hispanic, 7.2% were black, 1.12% were Asian, and 4% were classified as "other."

All patients had undergone an electrocardiogram (ECG) 14 to 90 days after receiving a prescription for 1 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 correct QT interval is normally less than 420 milliseconds for men and less than 440 milliseconds for women.

Results showed that a significantly longer than normal QT interval was found for the patients receiving the selective serotonin reuptake inhibitors (SSRIs) citalopram (P < .01) and escitalopram (P < .001), the tricyclic antidepressant amitriptyline (P < .001), and methadone (P < .001).

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

"Nearly one in five patients treated with these antidepressants who underwent [ECG] had QT intervals which would be considered abnormal," write the investigators. However, they note 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 < .05).

"This was surprising, but as we delved into the literature, it made a certain amount of sense based on what people had observed studying the drug. It just hadn't really been reported before," said Dr. Perlis.

No effect on QT interval was shown for any dose of fluoxetine, paroxetine, sertraline, duloxetine, mirtazapine, nortriptyline, and venlafaxine.

Overall, this study "confirmed a modest prolongation of QT interval with citalopram, and identified additional antidepressants with similar observed risk," write the researchers.

"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 Dr. 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 real message to patients taking these drugs is to have a discussion with their doctors."

He also noted the benefits of using electronic health records to answer important research questions.

"Finding the QT-shortening effects of bupropion shows how this approach can help us to find drugs with unexpected benefits and not just unexpected problems," he said.

Dr. Perlis added that although this strategy's limitations include the fact that individuals are not randomly assigned to different treatment arms, it does allow researchers to study a greater number of patients and to get answers much faster.

"In terms of patient privacy, this is actually much safer than the older methods, which required a person look through a pile of medical records one by one. This way we only extract the data we need and never see anything that would allow us to identify an individual patient," he said.

"Doing this by hand...would have taken a year or more. Doing it with electronic health records took about an hour."

The study was funded by grants from the National Institutes of Health/National Library of Medicine and from the National Institute of Mental Health. A complete list of financial disclosures is available in the original article.

Br J Psychiatry. Published online January 29, 2013. Abstract