A rational preclinical basis for maximising cardiac safety in citalopram use

Citalopram and its S(+) enantiomer escitalopram are selective serotonin reuptake inhibitors (SSRIs) very widely used clinically to treat depression and some anxiety disorders.

Clinical use of these drugs has been linked to dose-dependent QT prolongation, whilst case reports and pharmacovigilance databases have documented cases of torsades de pointes (TdP) arrhythmia.

We have shown that, like the racemate and S(+) enantiomer, R(-) citalopram inhibits hERG K+ channels, which are strongly implicated in drug-induced QT prolongation.

It is striking that racemic citalopram remains so highly prescribed in the UK and elsewhere: R(-) citalopram has no therapeutic benefit, may exert detrimental actions on cardiac repolarization, but has not been directly studied in this regard.

We propose an integrated preclinical study that will provide a rational basis for informed pharmacological choice to maximise cardiac safety in (es)citalopram use.

It will compare effects of citalopram, escitalopram, R(-) citalopram, and citalopram’s main metabolite on hERG channel electrophysiology (alone and with accessory protein variants linked to drug-induced QT prolongation) and trafficking and upon the electrophysiology of hiPSC-cardiomyocytes.

The results will inform future citalopram formulation selection, potentially including withdrawal or restriction of currently used formulations including the (R-) enantiomer, to minimise cardiac arrhythmia risk.