Recently, I was critically reminded of the effect that certain medications have on the QT interval. My longtime patient with a history of depression and insomnia presented to me with chest pain symptoms. An ECG was ordered. Within an hour, our QT prolongation warning system notified me that her corrected QT interval (QTc) had prolonged to 530 milliseconds. Her previous QTc was 479 milliseconds. Electrolytes were normal. She was taking paroxetine for depression and trazodone for insomnia. Both were tapered and discontinued over the next several days, with return of her QTc to 473 milliseconds. Crisis averted.
A prolonged QT interval reflects abnormal repolarization (electrical recharging) and may lead to torsades de pointes and sudden cardiac death. A long QT interval can be associated with congenital long QT syndrome, electrolyte abnormalities, or medications. The greatest risk factors for an adverse event such as sudden death or aborted cardiac arrest are associated with a QTc of more than 500 milliseconds and a history of nonvasovagal syncope.
In my patient population surviving into their later years, iatrogenic causes of prolonged QTc are far and away the most common etiologies. And with my patient population either becoming more depressed – or me becoming more adept at diagnosing it – antidepressants are high on the list of offenders.
So which ones are the ones that we should be most concerned about? And is there a dose effect?
Dr. Victor M. Castro and his team published a case-control study (BMJ 2013;346:f288) quantifying the impact of citalopram and other selective serotonin reuptake inhibitors on the QT interval. Patients were at least 18 years of age with at least one prescription of an antidepressant or methadone between 1990 and 2011. Methadone is known to prolong the QT interval and was used to verify the sensitivity of the analysis.
The antidepressants analyzed were citalopram, escitalopram, fluoxetine, paroxetine, sertraline, amitriptyline, bupropion, duloxetine, mirtazapine, nortriptyline, and venlafaxine. Patients’ ECGs were selected for analysis if they occurred at least 14 days after a prescription. Of the study patients receiving a medication of interest, 38,397 patients had an ECG in the specified 14- to 90-day window. Analyses of QTc were adjusted for potential confounders such as preexisting cardiovascular disease.
In this population, 20.4% of individuals were characterized as having abnormal or high QTc values. Methadone predictably increased QTc. Dose was observed to be a significant predictor of QTc with citalopram (10-20 mg), escitalopram (5-10 mg and 10-20 mg), and amitriptyline (25-50 mg). Bupropion was found to significantly decrease QTc (P less than .05). Notably, 13.1% of patients who started citalopram with a QTc in the normal range shifted to abnormal after a dose increase.
In this study, one-fifth of patients had an abnormal QTc. But QTc is only considered a proxy measure for torsades de pointes. So, whether we should be routinely ordering ECGs for patients started on citalopram, escitalopram, or amitriptyline, or for whom the dose of these drugs has been changed, remains uncertain.
When my patient’s depression ferociously returned, I restarted paroxetine. This time, I ordered a follow-up ECG, which showed no QT prolongation. Crisis averted.