Escitalopram versus citalopram: the surprising role of the R-enantiomer (original) (raw)
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Basic <html_ent glyph="@amp;" ascii="&"/> Clinical Pharmacology <html_ent glyph="@amp;" ascii="&"/> Toxicology, 2006
Recent results on the in vivo and in vitro pharmacology of escitalopram are summarised. The exact molecular mechanism by which R-citalopram inhibits the effect of S-citalopram on the serotonin transporter remains to be elucidated. Preliminary evidence indicates an effect of R-citalopram on the association of escitalopram with the high affinity primary site, and on its dissociation from the serotonin transporter, via an allosteric mechanism. Escitalopram can be considered as an allosteric serotonin reuptake inhibitor. This serotonin dual action in binding to two sites on the serotonin transporter (both the primary site and the allosteric site) is hypothesised to be responsible for a longer binding to, and therefore greater inhibition of the serotonin transporter by escitalopram.
Comparison of escitalopram and citalopram efficacy: A meta-analysis
International Journal of Psychiatry in Clinical Practice, 2003
OBJECTIVE: Escitalopram is a new selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of major depressive disorder (MDD) and panic disorder. Escitalopram is the therapeutically active enantiomer of citalopram. Its efficacy in the treatment of MDD was compared to that of citalopram.
British Journal of Pharmacology, 2004
1 Clinical observations with the selective serotonin reuptake inhibitor (SSRI), S-citalopram, indicate that S-citalopram is more efficacious and produces earlier symptom relief than RS-citalopram. Since R-citalopram is at least 20-fold weaker than S-citalopram as inhibitor of the 5-HT transporter (SERT) in preclinical studies, the clinical data suggest an unexpected antagonistic interaction between the two enantiomers. We therefore characterised the interaction of R-and S-citalopram with the SERT in in vivo and in vitro assays. 2 In both behavioural (potentiation of 5-hydroxytryptophan (5-HTP)-induced behaviour) and electrophysiological studies (inhibition of 5-HT-elicited ion currents in Xenopus oocytes expressing the human SERT (hSERT) R-citalopram inhibited the effects of S-citalopram in a dose-dependent manner. With S-citalopram : R-citalopram ratios of 1 : 2 and 1 : 4, 5-HTP potentiation was significantly smaller than with S-citalopram alone. 3 R-citalopram did not antagonise the effects of another SSRI (fluoxetine) in either behavioural or electrophysiological studies. 4 In oocytes, inhibition of hSERT-mediated currents by R-citalopram was almost completely reversible and characterised by fast on-and off-sets of action. In contrast, the off-set for S-citalopram was 35-fold slower than for R-citalopram. 5 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. 6 We propose that the kinetic interaction of R-and S-citalopram with SERT is a critical factor contributing to the antagonistic effects of R-citalopram on S-citalopram in vitro and in vivo.
Psychopharmacology, 2007
Objectives Previous studies have investigated the occupancy of the serotonin reuptake transporter (SERT) after clinical doses of citalopram and other selective serotonin reuptake inhibitors. In the present study, the occupancies of SERT after multiple doses of escitalopram and citalopram were compared using the radioligand [123I]ADAM and single photon emission computed tomography (SPECT). Methods Fifteen healthy subjects received escitalopram 10 mg/day (n = 6) or citalopram 20 mg/day (n = 9) for a total of 10 days. SERT occupancies in midbrain were determined with SPECT and [123I]ADAM at three different time points: at baseline (no medication) and at 6 and 54 h after last drug intake. Results At 6 h after the last dose, mean SERT occupancies were 81.5 ± 5.4% (mean±SD) for escitalopram and 64.0 ± 12.7% for citalopram (p < 0.01). At 54 h after the last dose, mean SERT occupancies were 63.3 ± 12.1% for escitalopram and 49.0 ± 11.7% for citalopram (p < 0.05). The plasma concentrations of the S-enantiomer were of the same magnitude in both substances. For both drugs, the elimination rate of the S-enantiomer in plasma was markedly higher than the occupancy decline rate in the midbrain. Conclusion The significantly higher occupancy of SERT after multiple doses of escitalopram compared to citalopram indicates an increased inhibition of SERT by escitalopram. The results can also be explained by an attenuating effect of R-citalopram on the occupancy of S-citalopram at the SERT.
International Clinical Psychopharmacology, 2009
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, highaffinity 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.
European Neuropsychopharmacology, 2005
The interaction of the S-and R-enantiomers (escitalopram and R-citalopram) of citalopram, with high-and low-affinity binding sites in COS-1 cell membranes expressing human SERT (hSERT) were investigated. Escitalopram affinity for hSERT and its 5-HT uptake inhibitory potency was in the nanomolar range and approximately 40-fold more potent than R-citalopram. Escitalopram considerably stabilised the [ 3 H]-escitalopram/SERT complex via an allosteric effect at a low-affinity binding site. The stereoselectivity between escitalopram and Rcitalopram was approximately 3:1 for the [ 3 H]-escitalopram/hSERT complex. The combined effect of escitalopram and R-citalopram was additive. Paroxetine and sertraline mainly stabilised the [ 3 H]-paroxetine/hSERT complex. Fluoxetine, duloxetine and venlafaxine have only minor effects. 5-HT stabilised the [ 125 I]-RTI-55, [ 3 H]-MADAM, [ 3 H]-paroxetine, [ 3 H]-fluoxetine and [ 3 H]-venlafaxine/SERT complex to some extent. Thus, escitalopram shows a unique interaction with the hSERT compared with other 5-HT reuptake inhibitors (SSRIs) and, in addition to its 5-HT reuptake inhibitory properties, displays a pronounced effect via an affinity-modulating allosteric site. D
European Neuropsychopharmacology, 2013
According to both in vitro and in vivo data P-glycoprotein (P-gp) may restrict the uptake of several antidepressants into the brain, thus contributing to the poor success rate of current antidepressant therapies. The therapeutic activity of citalopram resides in the S-enantiomer, whereas the R-enantiomer is practically devoid of serotonin reuptake potency. To date, no in vivo data are available that address whether the enantiomers of citalopram and its metabolites are substrates of P-gp. P-gp knockout (abcb1ab (-/-)) and wild-type (abcb1ab (+/+)) mice underwent acute (single-dose) and chronic (two daily doses for 10 days) treatment with citalopram (10 mg/kg) or escitalopram (5 mg/kg). Serum and brain samples were collected 1-6 h after the first or last i.p. injection for subsequent drug analysis by an enantioselective HPLC method. In brain, 3-fold higher concentrations of Sand R-citalopram, and its metabolites, were found in abcb1ab (-/-) mice than in abcb1ab (+/+) mice after both acute and chronic citalopram treatments. After escitalopram treatment, the S-citalopram brain concentration was 3-5 times higher in the knockout mice than in controls. The results provide novel evidence that the enantiomers of citalopram are substrates of P-gp. Possible clinical and toxicological implications of this finding need to be further elucidated.
Escitalopram for the treatment of major depression and anxiety disorders
Expert Review of Neurotherapeutics, 2008
Escitalopram is the S-enantiomer of the selective serotonin reuptake inhibitor (SSRI) citalopram, which contains equal amounts of the Sand R-forms in a racemic mixture. Escitalopram is the most selective SSRI, with almost no significant affinity to other tested receptors. It has been demonstrated that it is escitalopram that carries the therapeutic potential of citalopram, and has statistically superior and clinically relevant properties compared with citalopram. Escitalopram is at least as effective in the treatment of depression and anxiety as other SSRIs, as well as venlafaxine, bupropion and duloxetine. Owing to multiple metabolic degrading pathways, the clinically relevant interactions of escitalopram with other drugs are minimal. Compared with other antidepressants, escitalopram is generally better tolerated, its onset of action is relatively fast, and its use may have cost-effectiveness and cost-utility advantages. Escitalopram is an effective first-line option in the management of patients with major depression, including severe forms, and various anxiety disorders.
Dear Doctor Letters regarding citalopram and escitalopram: guidelines vs real-world data
European Archives of Psychiatry and Clinical Neuroscience, 2022
Dear Doctor Letters (DDLs, Direct Healthcare Professional Communications) from 2011 provided guidance regarding QTc-prolonging effects with risk of torsade de pointes during treatment with citalopram and escitalopram. This study examines the DDLs’ effects on prescription behavior. Data from 8842 inpatients treated with citalopram or escitalopram with a primary diagnosis of major depressive disorder (MDD) were derived from a European pharmacovigilance study (Arzneimittelsicherheit in der Psychiatrie, AMSP) from 2001 to 2017. It was examined to what extent new maximum doses were adhered to and newly contraindicated combinations with QTc-prolonging drugs were avoided. In addition, the prescriptions of psychotropic drugs before and after DDLs were compared in all 43,480 inpatients with MDD in the data set. The proportion of patients dosed above the new limit decreased from 8 to 1% in patients ≤ 65 years and from 46 to 23% in patients > 65 years old for citalopram versus 14–5% and 47–...