Escitalopram the S-enantiomer of the racemate
citalopram, is clinically more effective than
citalopram in the treatment of
major depressive disorder. However, the precise mechanism by which
escitalopram achieves superiority over
citalopram is yet to be determined. It has been hypothesized that the therapeutically inactive R-enantiomer competes with the
serotonin-enhancing S-enantiomer at a low-affinity allosteric site on
serotonin reuptake transporters (SERTs), and reduces the effectiveness of the S-enantiomer at the primary, high-affinity
serotonin-binding site. This study summarizes the results of two recent single-photon emission computerized tomography studies measuring SERT occupancy in
citalopram-treated and
escitalopram-treated healthy volunteers, after a single dose and multiple doses (i.e. under steady-state conditions). The single-dose study showed no attenuating effect of R-
citalopram. After multiple dosing, however, SERT occupancy was significantly reduced in the presence of R-
citalopram. Under steady-state conditions, R-enantiomer concentrations were greater than for the S-enantiomer because of slower clearance of R-
citalopram. A pooled analysis suggests that build-up of the R-enantiomer after repeated
citalopram dosing may lead to increased inhibition of S-enantiomer occupancy of SERT. This review adds to the growing body of evidence regarding differences in the dynamics of SERT occupancy, that is, molecular mechanisms underlying the often-observed superior clinical efficacy of
escitalopram compared with
citalopram in
major depressive disorder.