Higher serotonin transporter occupancy after multiple dose administration of escitalopram compared to citalopram: An [123I]ADAM SPECT study

Department of General Psychiatry, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
Psychopharmacology (Impact Factor: 3.88). 05/2007; 191(2):333-9. DOI: 10.1007/s00213-006-0666-y
Source: PubMed


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 [(123)I]ADAM and single photon emission computed tomography (SPECT).
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 [(123)I]ADAM at three different time points: at baseline (no medication) and at 6 and 54 h after last drug intake.
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.
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.

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    • "Studies in small laboratory animals and non-human primates have shown that the in vivo binding of [123/125I]ADAM is selective for SERTs [2, 3]. In addition, preliminary studies in humans have shown that radiotracer binding in SERT-rich brain areas could be blocked by SSRIs [4, 5]. However, it has not been proven that [123I]ADAM binds selectively to SERTs in living human brain. "
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    ABSTRACT: The tracer (123)I-2-([2-({dimethylamino}methyl)phenyl]thio)-5-iodophenylamine ([(123)I]ADAM) has been developed to image serotonin transporters (SERTs) with SPECT. Preclinical studies have shown that [(123)I]ADAM binds selectively to SERTs. Moreover, initial human studies have shown that [(123)I]ADAM binding could be blocked by selective serotonin reuptake inhibitors (SSRIs). However, in humans it has not been proven that [(123)I]ADAM binds selectively to SERTs. We examined the in vivo availability of SERTs in 12 healthy young volunteers 5 h after bolus injection of [(123)I]ADAM. To evaluate the selectivity of binding, four participants were pretreated (double-blinded design) with placebo, four with paroxetine (20 mg) and four with the dopamine/norepinephrine blocker methylphenidate (20 mg). SPECT studies were performed on a brain-dedicated system (Neurofocus), and the SPECT images were coregistered with individual MR scans of the brain. ADAM binding in SERT-rich brain areas and cerebellar cortex (representing non-specific binding) was assessed by drawing regions of interest (ROIs) on the individual MR images. Specific to non-specific ratios were used as the outcome measure. We found that specific to non-specific ratios were statistically significantly lower in paroxetine-pretreated participants than in placebo- or methylphenidate-pretreated participants. No such difference was found between groups pretreated with placebo or methylphenidate. Our preliminary findings suggest that [(123)I]ADAM binds selectively to SERTs in human brain.
    European Journal of Nuclear Medicine 03/2010; 37(8):1507-11. DOI:10.1007/s00259-010-1424-2 · 5.38 Impact Factor
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    • "Therefore, more rapid desensitization of the receptors, as observed with escitalopram, could lead to a faster onset of action (El Mansari et al., 2005). Summary points for escitalopram versus citalopram: (i) escitalopram (S-enantiomer) has improved pharmacological potency as a serotonin reuptake inhibitor in vitro versus the R-enantiomer; the S-enantiomer has the benefit of allosterically modulating the SERT; (Hyttel et al., 1992) (ii) the R-enantiomer is metabolized more slowly than the S-enantiomer (Sidhu et al., 1997), resulting in approximately two-fold higher plasma concentration of the R-enantiomer (Overo, 1982; Tanum et al., 2003); (iii) R-citalopram may have a functional antagonistic effect on escitalopram (Cremers and Westerink, 2003; El Mansari et al., 2005; Lucki and Brown, 2003; Mørk et al., 2003;) with significantly higher occupancy 6 h post-dose with escitalopram (10 mg/day: 82%) compared with citalopram (20 mg/day: 64%) (Klein et al., 2007; Meyer et al., 2004); (iv) R-citalopram should not be considered an inactive enantiomer: it may have a deleterious influence on the activity of escitalopram through functional antagonism (El Mansari et al., 2007); (v) escitalopram may have a faster onset of action than citalopram (Sanchez, 2003; Sanchez et al., 2003a, b) as a result of more rapid desensitization of 5-hydroxytryptamine 1A subtype autoreceptors, leading to more rapid disinhibition of the serotonergic neurones, and enhanced release of serotonin (Blier and Bouchard, 1994). "
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    ABSTRACT: The majority of currently marketed drugs contain a mixture of enantiomers; however, recent evidence suggests that individual enantiomers can have pharmacological properties that differ importantly from enantiomer mixtures. Escitalopram, the S-enantiomer of citalopram, displays markedly different pharmacological activity to the R-enantiomer. This review aims to evaluate whether these differences confer any significant clinical advantage for escitalopram over either citalopram or other frequently used antidepressants. Searches were conducted using PubMed and EMBASE (up to January 2009). Abstracts of the retrieved studies were reviewed independently by both authors for inclusion. Only those studies relating to depression or major depressive disorder were included. The search identified over 250 citations, of which 21 studies and 18 pooled or meta-analyses studies were deemed suitable for inclusion. These studies reveal that escitalopram has some efficacy advantage over citalopram and paroxetine, but no consistent advantage over other selective serotonin reuptake inhibitors. Escitalopram has at least comparable efficacy to available serotonin-norepinephrine reuptake inhibitors, venlafaxine XR and duloxetine, and may offer some tolerability advantages over these agents. This review suggests that the mechanistic advantages of escitalopram over citalopram translate into clinical efficacy advantages. Escitalopram may have a favourable benefit-risk ratio compared with citalopram and possibly with several other antidepressant agents.
    Journal of Psychopharmacology 02/2010; 24(8):1143-52. DOI:10.1177/0269881109349835 · 3.59 Impact Factor
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    • "This concentration of R-citalopram is within the range measured during the treatment with citalopram (Sidhu et al., 1997). Klein et al. (2007) estimated the occupancy decline rate to be approximately 130 h, based on midbrain SERT occupancies at the 6 and 54 h timepoints in the multipledose study; the plasma elimination half-life, however, was approximately 25 h. Although it is difficult to compare plasma and brain kinetics, as only the former follows the first-order kinetics, repeated dosing seems to lead to a higher brain/plasma ratio of escitalopram. "
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    ABSTRACT: 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.
    International clinical psychopharmacology 06/2009; 24(3):119-25. DOI:10.1097/YIC.0b013e32832a8ec8 · 2.46 Impact Factor
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