Escitalopram, a selective serotonin reuptake inhibitor, is the pharmacologically 
active S-enantiomer of the racemic mixture of RS-citalopram and is widely used 
in the treatment of depression. The effects of escitalopram and citalopram on 
the human ether-a-go-go-related gene (hERG) channels expressed in human 
embryonic kidney cells were investigated using voltage-clamp and Western blot 
analyses. Both drugs blocked hERG currents in a concentration-dependent manner 
with an IC50 value of 2.6 μM for escitalopram and an IC50 value of 3.2 μM for 
citalopram. The blocking of hERG by escitalopram was voltage-dependent, with a 
steep increase across the voltage range of channel activation. However, voltage 
independence was observed over the full range of activation. The blocking by 
escitalopram was frequency dependent. A rapid application of escitalopram 
induced a rapid and reversible blocking of the tail current of hERG. The extent 
of the blocking by escitalopram during the depolarizing pulse was less than that 
during the repolarizing pulse, suggesting that escitalopram has a high affinity 
for the open state of the hERG channel, with a relatively lower affinity for the 
inactivated state. Both escitalopram and citalopram produced a reduction of hERG 
channel protein trafficking to the plasma membrane but did not affect the 
short-term internalization of the hERG channel. These results suggest that 
escitalopram blocked hERG currents at a supratherapeutic concentration and that 
it did so by preferentially binding to both the open and the inactivated states 
of the channels and by inhibiting the trafficking of hERG channel protein to the 
plasma membrane.