Editor’s note: We’re pleased to introduce the new feature “Uncommon Tips.” In this series, Dr. Aiken will discuss little-known pearls about commonly used medications. The series starts with a comparison of citalopram and escitalopram.

The rivalry between these two SSRIs began in 2002 when the Lundbeck pharmaceutical company split citalopram (Celexa) into its two mirror-image enantiomers, releasing the active enantiomer (escitalopram) as Lexapro and leaving behind the inactive one (R-citalopram). With Celexa’s patent about to expire and Lexapro’s extended for another decade, Lundbeck scurried to convince doctors that escitalopram was the better choice.

Lundbeck argued that R-citalopram was not a neutral bystander but actually interfered with escitalopram’s ability to raise serotonin by blocking it at the serotonin transporter. The evidence came from animal studies, but it seemed confirmed by a series of head-to-head clinical trials showing slightly higher efficacy and faster onset with escitalopram than citalopram in major depression and panic disorder (Sánchez C et al, Psychopharmacology (Berl) 2004;174(2):163–176).

How well has that claim held up? Marginally. Although most of the 10 trials comparing the two SSRIs favor escitalopram, the difference is slight. When narrowed down to equidose comparisons (eg, citalopram 40 mg vs escitalopram 20 mg), only 5%–10% of patients have a meaningful response on escitalopram that they wouldn’t have experienced on citalopram (Trkulja V, Croat Med J 2010;51(1):61–73).

Instead, a different reason to prefer escitalopram has arisen from the FDA, which placed a warning about QTc prolongation on citalopram in 2011. This risk is dose dependent, so the FDA capped citalopram’s dose at 40 mg/day, or 20 mg/day in patients who are (1) over age 60; (2) poor metabolizers at the CYP2C19 enzyme that clears citalopram; or (3) taking strong CYP2C19 inhibitors like omeprazole or cimetidine.

However, the FDA’s dosing guidelines can have unintended consequences. When the VA attempted to lower citalopram into the acceptable range for 35,848 veterans, they saw a sharp increase in all-cause hospitalizations and deaths without any decline in arrhythmias (Rector TS et al, Am J Psychiatry 2016;173(9):896–902). What, then, is an FDA-abiding clinician to do?

One approach is to switch to escitalopram, which is free of this FDA warning because it only causes about half as much QTc prolongation as citalopram at equivalent doses (citalopram 60 mg = 18.5 ms; escitalopram 30 mg = 10.7 ms). Even though actual cardiac problems are very rare on either drug, there is evidence that this difference in QTc interval has a real-world effect on cardiac outcomes. Two studies that examined large, diverse populations found higher rates of cardiac arrest and serious arrhythmias with citalopram than escitalopram (Qirjazi E et al, PLoS One 2016;11(8):e0160768; Weeke P et al, Clin Pharmacol Ther 2012;92(1):72–79).

If you choose this route, I’d suggest a gradual cross-taper, such as adding in escitalopram at 5 mg and titrating to half the original citalopram dose while tapering citalopram off over two to four weeks. We don’t know much about the long-term effects of citalopram’s R-enantiomer, and sudden shifts in a stable pharmacodynamic system may have unintended consequences of their own.

CARLAT VERDICT

Escitalopram is generally safer and possibly more effective than citalopram, but psychiatric practice is full of the unexpected. Be careful if you decide to cross-taper from one to the other.