Differences in the dynamics of serotonin reuptake transporter occupancy may explain superior clinical efficacy of escitalopram versus citalopram

  title={Differences in the dynamics of serotonin reuptake transporter occupancy may explain superior clinical efficacy of escitalopram versus citalopram},
  author={Siegfried Kasper and Julia Sacher and Nikolas Klein and Nilufar Mossaheb and Trawat Attarbaschi-Steiner and Rupert Lanzenberger and Christoph Spindelegger and Susanne Asenbaum and Alexander Holik and Robert Dudczak},
  journal={International Clinical Psychopharmacology},
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… 
Escitalopram, an antidepressant with an allosteric effect at the serotonin transporter—a review of current understanding of its mechanism of action
The findings from binding, neurochemical, and neurophysiological studies may provide a mechanistic rationale for the clinical difference observed with escitalopram compared to other antidepressant therapies.
Towards limiting QT interval prolongation and arrhythmia risk in citalopram use.
Data from studies, in which serotonin reuptake transporter (SERT) occupancy has been examined in humans, suggest that on repeated dosing with racemic citalopram, R(–) cITALopram levels may exceed those of the S(+) enantiomer, leading to reduced S(+) citalsopram occupancy of SERT.
Serum concentrations of citalopram--dose-dependent variation in R- and S-enantiomer ratios.
The findings show that the stereoselective metabolism of citalopram IN VIVO has pharmacokinetic consequences reflected by dose dependent variations of enantiomeric drug concentrations, as well as substantial interindividual variabilities in the ratios of the concentrations.
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Escitalopram, like other SSRIs, is an effective first-line option in the management of patients with MDD, and has a predictable tolerability profile with generally mild to moderate and transient adverse events, and a low propensity for drug interactions.
Plasma Concentrations and Cardiovascular Effects of Citalopram Enantiomers after Oral vs. Infusion Citalopram Therapy in Dextromethorphan- and Mephenytoin-Phenotyped Patients with Major Depression.
Owing to CLT's high bioavailability, the plasma concentrations of its enantiomers remained largely independent on the administration route and no relationship was found between any cardiovascular parameters and pharmacokinetic and pharmacogenetic data.
Regional differences in SERT occupancy after acute and prolonged SSRI intake investigated by brain PET
A comparative review of escitalopram, paroxetine, and sertraline: are they all alike?
Overall, as an allosteric serotonin reuptake inhibitor that is somewhat different from classical SSRIs, escitalopram is the first choice judged by combined efficacy and tolerability, and nonclinical data have offered possible mechanisms through which escITALopram could be more efficacious.
R- and S-citalopram concentrations have differential effects on neuropsychiatric scores in elders with dementia and agitation.
The results suggest that citalopram enantiomers contributed differentially to treatment outcomes as measured by the CGIC and a reduction in MMSE scores.
ABCB1 gene polymorphisms are associated with the severity of major depressive disorder and its response to escitalopram treatment
It is suggested that single nucleotide polymorphisms in the ABCB1 gene may be indicators of the severity of depression and of the likely S-CIT treatment remission response in MDD.
Stereo‐Psychopharmacology: The Case of Citalopram and Escitalopram
“Chiral switching” is generally defined as the marketing of a single-enantiomer (enantiopure) derivative of a racemic drug that has already been approved.1–3 For example, the proton pump inhibitor


Higher serotonin transporter occupancy after multiple dose administration of escitalopram compared to citalopram: an [123I]ADAM SPECT study
The significantly higher occupancy of SERT after multiple doses of escITALopram compared to citalopram indicates an increased inhibition of Sert by escitalopra, and the elimination rate of the S-enantiomer in plasma was markedly higher than the occupancy decline rate in the midbrain.
Allosteric modulation of the effect of escitalopram, paroxetine and fluoxetine: in-vitro and in-vivo studies.
In-vitro and in-vivo studies show that R-citalopram counteracts the activity of escitaloprams and paroxetine, but not fluoxettine, by acting at the allosteric binding site of the 5-HT transporter, either located in the dorsal raphe nucleus or post-synaptically in the ventral hippocampus.
Escitalopram versus citalopram: the surprising role of the R-enantiomer
The R- enantiomer present in citalopram counteracts the activity of the S-enantiomer, thereby providing a possible basis for the pharmacological and clinical differences observed between citalobram and escitaloprams.
In vivo imaging of serotonin transporter occupancy by means of SPECT and [123I]ADAM in healthy subjects administered different doses of escitalopram or citalopram
SPECT and [123I]ADAM and single photon emission computer tomography were used to investigate SERT occupancies after single doses of escitalopram or citaloprams, and good reproducibility of SERT quantification was revealed.
R-citalopram inhibits functional and 5-HTP-evoked behavioural responses to the SSRI, escitalopram
Efficacy Comparison of Escitalopram and Citalopram in the Treatment of Major Depressive Disorder: Pooled Analysis of Placebo-Controlled Trials
Evaluated data suggest escitalopram may have a faster onset and greater overall magnitude of effect than citaloprams in improving symptoms of depression and anxiety in patients with major depressive disorder.
R‐citalopram functionally antagonises escitalopram in vivo and in vitro: evidence for kinetic interaction at the serotonin transporter
Kinetic analysis of the oocyte experiments suggests that S‐citalopram binding to SERT induces a long‐lasting, inhibited state of the transporter and that coapplication of R‐cITALopram partially relieves SERT of this persistent inhibition.
R-citalopram counteracts the antidepressant-like effect of escitalopram in a rat chronic mild stress model
EscITALopram showed a shorter time to response in the rat CMS model of depression than citalopram, which was faster acting than R-fluoxetine and imipramine, and may also indicate an earlier response to escitaloprams compared to other selective serotonin reuptake inhibitors (SSRIs).