Abstract
The antidepressant citalopram, a selective serotonin reuptake inhibitor (SSRI), has been associated with increased risk of sudden cardiac death. Epidemiological data from the Danish population suggest that in patients taking citalopram, co-administration of carvedilol reduced sudden death risk compared to two other beta-blockers, metoprolol and bisoprolol. Since carvedilol is the only beta blocker that suppresses store overload-induced calcium release, we hypothesized that citalopram promotes calcium release from sarcoplasmic reticulum (SR) calcium stores. Left ventricular myocytes were isolated from black 6 mice, permeabilized, and loaded with the calcium indicator, Fluo-4. Incubation of citalopram or escitalopram (S-enantiomer) for 20 minutes significantly increased calcium wave frequency and decreased calcium wave amplitude in a dose-dependent manner. This response was more sensitive to escitalopram, indicating selectivity for the S-enantiomer in the high nanomolar range. At 30 µM, calcium waves were no longer evident, however cytosolic calcium was elevated approximately two-fold, indicating possible constitutive calcium release from the SR stores. Incubation with a different SSRI, paroxetine, did not significantly alter calcium wave frequency or amplitude at concentrations as high as 30 µM. Calcium wave activation by citalopram and escitalopram resembled those seen in a calsequestrin knockout mouse model of catecholaminergic polymorphic ventricular tachycardia (CPVT), suggesting a possible similar mechanism for citalopram. Pre-incubation of isolated myocytes with 1 µM carvedilol, but not metoprolol or bisoprolol, for 30 minutes significantly reduced calcium wave frequency and increased SR calcium stores in myocytes treated with citalopram or escitalopram. Taken together, increased calcium leak from SR stores through ryanodine receptor may contribute to the increased risk of sudden death associated with citalopram. Hence, our in vitro findings support the existence of drug-induced CPVT caused by citalopram or escitalopram, which can be prevented by co-administration of carvedilol.
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