Therapeutic doses of some selective serotonin reuptake inhibitors (SSRIs) may lead to cardiotoxic concentration levels associated with increased risk of arrhythmia in certain groups of patients, including those 65 and up, according to a Norwegian cohort study.

In patients 65 and over taking escitalopram (Lexapro) daily, about 20% were predicted to reach potentially pro-arrhythmic concentrations with a 10-mg dose, which increased to about 60% with a 20-mg dose, reported Erik Sveberg Dietrichs, MD, PhD, of the Center for Psychopharmacology at Diakonhjemmet Hospital in Oslo, and co-authors in eBioMedicine.

“We show that therapeutic concentrations of escitalopram have pro-arrhythmic potential in vitro by increasing triangulation of the human cardiac action potential, which is related to increased risk for Torsade de Pointes and cardiac arrest,” Dietrichs told MedPage Today. “This is a known side effect of escitalopram, leading to FDA recommendations that doses above 20 mg should be avoided.”

According to the FDA’s labeling for the drug, the recommended dosage in most elderly patients is 10 mg per day, with maximum doses of 20 mg per day in adolescents and younger adults.

Dietrichs noted that age-based variations in the dose-adjusted serum concentrations of escitalopram — and citalopram (Celexa) — suggested that patients are reaching potentially cardiotoxic concentrations despite using recommended doses.

The study authors pointed out that age was a key factor in the proportion of patients above those thresholds, due to age-dependent reductions in drug clearance.

According to their analysis, the percentage of patients taking a daily dose of 20-mg escitalopram predicted to exceed the threshold for pro-arrhythmic activity increased with each age group: 28% in <18 years, 43% in 18-64 years, 57% in 65-79 years, and 60% in ≥80 years.

These findings suggest that all patients that are using escitalopram or citalopram who are over age 65, using additional pro-arrhythmic drugs, or have predisposition for arrhythmias should receive therapeutic drug monitoring (TDM) to avoid increased exposure to cardiotoxic concentrations, especially patients with genetic disposition for acquired long-QT syndrome.

“Escitalopram is the most commonly used antidepressant in Norway, and is commonly used by patients all over the world, including the U.S.,” said Dietrichs. “As these drugs generally are well tolerated and important for treatment of a large patient group, we want to increase safety of such treatment, by enabling clinicians to detect patients at risk for serious adverse events.”

Serum concentrations of escitalopram should be kept below 100 nM in order to avoid these pro-arrhythmic effects, he added, emphasizing that patients with known QT-prolongation should completely avoid these drugs.

For this study, the researchers used observed drug and metabolite serum concentrations from a Norwegian cohort of 19,742 patients ages 12-105 from 2010 to 2019. Patients had to have a TDM measurement of escitalopram or citalopram within the limits of quantification for inclusion.

They analyzed the arrhythmogenic effects of citalopram, escitalopram, and their metabolites on human cardiomyocytes to determine thresholds for pro-arrhythmic activity, and compared those levels to the serum concentrations of escitalopram and citalopram in four age groups: <18 years, 18-64 years, 65-79 years, and ≥80 years.

They simulated the escitalopram maximum concentrations for each age group to determine the percentage of patients who would potentially exceed 136 nM, which corresponded with concentrations that significantly prolonged cardiac action potential.

Cardiac monitoring should be considered for patients who are determined to be at risk of arrhythmia, as should alternative antidepressant treatments, the authors concluded.

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