Differences in the dynamics of serotonin reuptake transporter occupancy may explain superior clinical efficacy of escitalopram versus citalopram.
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.
Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria. sci-biolpsy@meduniwien.ac.at
Siegfried
S
Kasper
Julia
J
Sacher
Nikolas
N
Klein
Nilufar
N
Mossaheb
Trawat
T
Attarbaschi-Steiner
Rupert
R
Lanzenberger
Christoph
C
Spindelegger
Susanne
S
Asenbaum
Alexander
A
Holik
Robert
R
Dudczak
D015283:Citalopram / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D011985:Receptors, Serotonin / Q000008:administration & dosage / Q000187:drug effects* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013237:Stereoisomerism; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
D015283:Citalopram; D011985:Receptors, Serotonin; D017367:Selective Serotonin Reuptake Inhibitors