Escitalopram: a unique mechanism of action

Abstract

The 5-HT (5-hydroxytryptamine, serotonin) transporter (SERT) mediates the reuptake of 5-HT from the synaptic cleft into the neuron, and inhibition of this uptake is the target of selective serotonin reuptake inhibitors (SSRIs). Escitalopram (S-citalopram) is the most selective SSRI available, whereas the other enantiomer, R-citalopram, is approximately 30–40 times less potent than the S-enantiomer. Both biochemical experiments (measurement of extracellular 5-HT in the frontal cortex of rats) and behavioural studies (using the chronic mild stress and conditioned fear stress models) demonstrate that R-citalopram appears to counteract the effect of escitalopram, and that it is a dose-dependent action. When escitalopram is administered at a specific dose, it produces a greater effect than when the same dose of the S-enantiomer is administered in combination with the R-enantiomer, i.e. when citalopram is administered. While mainly the S-enantiomer is bound to the primary binding site on the SERT, both enantiomers bind to the allosteric binding site. However, the R-enantiomer stabilises the binding of the S-enantiomer at the primary site less than the S-enantiomer. Furthermore, R-citalopram has an inhibitory effect on the association of escitalopram with the transporter, thereby possibly reducing escitalopram's effect. In summary, escitalopram appears to possess a unique mechanism of action at the 5-HT transporter protein. Furthermore, escitalopram (S-citalopram) is different from citalopram because R-citalopram counteracts the activity of the S-enantiomer.