![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 4 of 4. This is the beginning of the thread.
Posted by SLS on May 2, 2009, at 10:58:41
Hi.
Here is a recently published abstract I found that declares Lexapro (s-citalopram) is more effective than Celexa (racemic citalopram) because the r-citalopram enantiomer competes with the s-citalopram enantiomer for occupancy on the serotonin uptake transporter. R-citalopram does not inhibit the transporter from functioning, whereas s-citalopram does. Basically, r-citalopram is getting in the way of s-citalopram to inhibit the reuptake of serotonin.
- Scott
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Differences in the dynamics of serotonin reuptake transporter occupancy may explain superior clinical efficacy of escitalopram versus citalopramDudczak, Robert; Kasper, Siegfried; Sacher, Julia; Klein, Nikolas; Mossaheb, Nilufar; Attarbaschi-Steiner, Trawat; Lanzenberger, Rupert; Spindelegger, Christoph; Asenbaum, Susanne; Holik, Alexander
AbstractEscitalopram 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.
Posted by sdb on May 3, 2009, at 14:26:02
In reply to Lexapro more effective than Celexa - Why?, posted by SLS on May 2, 2009, at 10:58:41
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.
Introduction
The serotonergic system plays an important role in the pathophysiology of a number of psychiatric conditions, including major depressive disorder (MDD) (Kasper et al., 1990; Meyer et al., 2003), with or without dysfunctional attitudes, for example, self-injurious behaviour (Meyer et al., 2003), anxiety disorders (Neumeister et al., 2004; Lanzenberger et al., 2007) and schizophrenia (Kasper et al., 2002). Selective serotonin reuptake inhibitors (SSRIs) are recommended as first-line treatment for MDD and anxiety disorders, in line with best-practice clinical guidelines (Bandelow et al., 2002; Bauer et al., 2002; Baldwin et al., 2005). Drugs belonging to this class suppress the activity of serotonin reuptake transporters (SERTs), which regulate extracellular serotonin (5-HT) concentrations in the brain (Bel and Artigas, 1992, 1993, 1995; Dreshfield et al., 1996; Moret and Briley, 1996). SSRIs provide the sustained inhibition necessary to desensitize the presynaptic 5-HT autoreceptors found at serotonergic nerve terminals, enhancing the synaptic efficacy of the serotonergic system (Haddjeri et al., 1998; Pejchal et al., 2002).
It is estimated that the minimal blockade of SERTs required to exert a therapeutic effect corresponds to approximately 80% occupancy, as was determined from a positron emission tomography (PET) study using the SERT ligand [11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile ([11C]DASB) with multiple doses of four different SSRIs (citalopram, fluoxetine, sertraline and paroxetine) and venlafaxine XR, a serotoninnorepinephrine reuptake inhibitor, in patients with mood and anxiety disorders (Meyer et al., 2004). The SERT-binding affinities of these five drugs vary widely, and the estimated plasma concentration needed to obtain 50% SERT occupancy (EC50) was highest of citalopram (11.7 µg/l) and fluoxetine (14.8 µg/l). The authors found no significant linear correlation between EC50 and SERT occupancy for either actual or log-transformed values of binding affinities. Thus, it seems that SSRI plasma concentration alone can not account for the 80% threshold for the minimum therapeutic effect. Instead, the ability of SSRIs to penetrate the brain and accumulate around the synapses and axons, where SERTs are found in abundance (Zhou et al., 1998), was proposed as an important factor in predicting occupancy (Meyer et al., 2004).
Citalopram is a 1 : 1 racemic mixture of S(+)-citalopram and R(-)-citalopram; however, a number of studies showed that only the S-enantiomer (also known as escitalopram) is responsible for the pharmacological effects of the drug (Hyttel et al., 1992; Sanchez et al., 2003a, 2003b; Sanchez and Kreilgaard, 2004; Sanchez et al., 2004). This discovery led to the development of escitalopram as an antidepressant in its own right. Currently, both citalopram and escitalopram are licensed in Europe for the treatment of MDD, panic disorder and obsessivecompulsive disorder (only in some countries for citalopram) and in the United States for the treatment of MDD; escitalopram is also indicated for generalized anxiety disorder and social anxiety disorder.
A recent systematic review of pivotal studies and supporting meta-analyses reported definite superiority of escitalopram over other SSRIs, based on the highest quality evidence, in patients with moderate-to-severe depression (Montgomery et al., 2007). There is a growing body of evidence suggesting that escitalopram is more effective than an equivalent dosage of citalopram in treating MDD (Gorman et al., 2002; Lepola et al., 2003; Llorca et al., 2005; Moore et al., 2005; Kasper et al., 2006; Yevtushenko et al., 2007; Cipriani et al., 2009). Although the theory that chiral switching can provide clinical advantages is certainly an attractive one, some single-enantiomer agents have failed. For example, R-fluoxetine had potential superiority over fluoxetine for the treatment of MDD by virtue of a longer half-life and a reduced propensity for drugdrug interactions; however, its development was curtailed after studies highlighted a slightly increased risk of QT-interval prolongation compared with the racemate (Henry et al., 2005).
Although evidence for the superiority of escitalopram versus citalopram is becoming increasingly clearer (Kennedy et al., 2009), the mechanism is yet to be fully elucidated. Two possible explanations for the differences between citalopram and escitalopram have been proposed, which relate to the mechanism of action and midbrain SERT occupancy. The majority of studies have focused on the possibility that the R-enantiomer partially counteracts the actions of the S-enantiomer (Sanchez et al., 2004); whereas the S-enantiomer alone binds to the high-affinity, primary (serotonin-binding) site, both enantiomers bind to a lower affinity allosteric site and affect the binding of escitalopram to the primary site (Mansari et al., 2007). The R-enantiomer, thereby, may reduce the activity of the S-enantiomer (Sanchez et al., 2004).
Furthermore, it may be speculated that SERT occupancy could be more relevant than plasma concentration as a measure of SSRI activity. This possibility is supported by a study of the antipsychotic agents olanzapine and risperidone, which showed a significant difference between brain and plasma pharmacokinetics (Tauscher et al., 2002). Kugaya et al. (2004) showed in depressed patients that occupancy of diencephalic SERT by paroxetine (in contrast to plasma levels of paroxetine) correlated with treatment response assessed with the Hamilton Depression Rating Scale. Interestingly, they found that higher diencephalic SERT availability before treatment can be used as a predictive marker for better treatment response using single-photon emission computerized tomography (SPECT) and the radioligand [123I][beta]-CIT.
This study discusses the results of two recent studies that measured SERT occupancy in healthy young men given escitalopram or citalopram, and relates the findings to differences in clinical efficacy between these two preparations (Klein et al., 2006, 2007). A pooled analysis, in which both datasets are combined, investigated the time-dependent changes occurring at the SERT, comparing multiple dosing leading to steady-state conditions with single-dose administration.
Serotonin reuptake transporter occupancy and plasma pharmacokinetics after single and multiple doses of citalopram and escitalopramSERT occupancy and plasma pharmacokinetics were measured after administration of single (Klein et al., 2006) or multiple (Klein et al., 2007) equivalent doses of citalopram and escitalopram to healthy young men. In both the studies, occupancy in midbrain and hypothalamus was measured using basal SPECT with the radioligand 2-([2-([dimethylamino]methyl)phenyl]thio)-5-[123I]-iodophenylamine ([123I]ADAM). An earlier study showed that the ADAM ligand is the most selective ligand for SPECT imaging of SERTs, with a better signal-to-noise ratio than [123I][beta]-CIT (Sacher et al., 2007). The midbrain and hypothalamus were considered target regions of interest because of their highly specific 5-HT binding. The highly SERT-specific raphe nuclei were not used directly as target regions of interest, which presents a challenge in SPECT imaging at current best resolution. The cerebellum was used as the reference region, as specific serotonin binding here is low or nonexistent (Kish et al., 2005).
In the single-dose study (Klein et al., 2006), citalopram was given at doses of 10 and 20 mg and escitalopram at doses of 5, 10 and 20 mg (n = 5 in each dose group, with an additional four men receiving placebo for the purposes of testing reproducibility of the results). Volunteers refrained from smoking for at least 1 month and volunteers who reported a history of smoking were equally distributed throughout the groups. SERT occupancy was measured using [123I]ADAM SPECT imaging at baseline and 6 h after treatment, which was 7 days after the baseline visit. Binding potential was determined using a simplified reference tissue model, as previously described for SPECT imaging with [123I][beta]-CIT (Laruelle et al., 1993) and the ratio of specific to nonspecific binding was calculated. Drug levels in serum were measured immediately before dosing, and 2, 8 and 10 h after dosing. Interim measurements were also taken 30 min before and after the SPECT scan at 6 h post-dose (on average, approximately 3.5 h after tracer injection). An Emax model was used to describe the relationship between escitalopram levels in serum and SERT occupancy using the following equation:
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[Email Jumpstart To Image] Equation (Uncited)In this equation, Emax denotes maximum occupancy and S-CIT denotes escitalopram concentration immediately before the SPECT scan.
In the multiple-dose study (steady-state conditions), nine men received citalopram 20 mg/day and six received escitalopram 10 mg/day for a total of 10 days (Klein et al., 2007). The same screening procedure was applied as in the single-dose study. SERT occupancy was measured using SPECT imaging at baseline, and at 6 and 54 h after the final dose. Escitalopram levels in serum were measured on day 10 at the same timepoints as in the single-dose study, with additional measurements at 24 h after the final dose and 30 min before and after the third SPECT scan at 54 h. The techniques used in both studies to quantify SERT occupancy showed good reproducibility with an interclass correlation coefficient of 0.92 and a repeatability coefficient of 0.25%.
Results of the single-dose studySERT occupancy significantly increased in a dose-dependent manner with escitalopram dose (Table 1), whereas increases in SERT occupancy were also dose-dependent with citalopram, but not statistically significant. When comparing equimolar doses of each drug with respect to S-citalopram (i.e. 5 mg escitalopram vs. 10 mg citalopram, and 10 mg escitalopram vs. 20 mg citalopram), SERT occupancy was lower with escitalopram than with citalopram (60±6 vs. 65±10% and 64±6 vs. 70±6%, respectively, P>0.05 for both comparisons), indicating that there was no evidence of an attenuating effect of R-citalopram after single-dose administration of citalopram.
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[Email Jumpstart To Image] Table 1 Single-photon emission computerized tomography occupancyCIT, citalopram; ESC, escitalopram.a6 h after dosage.b6 h after last dosage.*P<0.05.**P<0.01 versus ESC20.***P<0.01 versus ESC10.
Results of the multiple-dose studyThe mean SERT occupancy was significantly higher after multiple dosing of escitalopram 10 mg/day than after citalopram 20 mg/day after the 10-day treatment period (Table 1), despite similar plasma concentrations of escitalopram. The corresponding results at 54 h post-final dose were 63.3±12.1% (escitalopram 10 mg) and 49.0±11.7% (citalopram 20 mg) (P = 0.04). Figure 1 shows the predicted and observed midbrain SERT occupancy for each treated individual at the 6 and 54h timepoints. EC50 was estimated to be 5.3±1.6 nmol/l (escitalopram 10 mg) and 5.7±1.8 nmol/l (citalopram 20 mg), with corresponding estimated Emax values of 89.6±5.7% (escitalopram 10 mg) and 71.8±4.8% (citalopram 20 mg) (Klein et al., 2007).
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[Email Jumpstart To Image] Fig. 1 Midbrain serotonin reuptake transporter (SERT) occupancy under steady-state conditions after 10 days administration of citalopram (20 mg/day; n = 9) or escitalopram (10 mg/day; n = 6). The graph shows individual data points and corresponding fitted Emax curves (89.6% for escitalopram vs. 71.8% for citalopram; P = 0.03). Results from day 10 (6 h after last dose) and day 12 (54 h after last dose) are shown together (Klein et al., 2007, Figure 2, p. 336. With kind permission of Springer Science+Business Media: Copyright Springer-Verlag 2007).Thus, 6 h after the 10th and final daily dose, SERT occupancy for escitalopram 10 mg (six of 12 data points in Fig. 1), but not citalopram 20 mg (nine of 18 data points), exceeded the 80% threshold thought to be necessary for clinical efficacy (Meyer et al., 2004), despite similar plasma concentrations of the S-enantiomer. This supports the hypothesis of an attenuating effect of the R-enantiomer on S-enantiomer SERT occupancy after multiple citalopram doses, and is in accordance with earlier findings that the pharmacodynamics of the S-enantiomer are different with escitalopram versus citalopram, because of the presence of the R-enantiomer when the latter is administered (Sanchez and Kreilgaard, 2004; Sanchez et al., 2004).
Dynamics of repeated exposure to citalopram and escitalopram on serotonin reuptake transporter occupancyA new post-hoc analysis of the datasets from the single-dosing and multiple-dosing studies was performed using nonlinear regression. Single-dosing and multiple-dosing results were pooled to demonstrate differences of the relationship between SERT occupancy and S-citalopram serum levels in the escitalopram (Fig. 2a) compared with the citalopram (Fig. 2b) group. SERT occupancy, as a function of escitalopram plasma concentration, was higher under steady-state conditions than after a single dose, although this difference was not statistically significant (Fig. 2a). SERT occupancy with citalopram was lower under steady-state conditions than after single administration; again, this difference was not statistically significant (Fig. 2b). SERT occupancy was significantly (P<0.05) higher with escitalopram compared with citalopram at equivalent doses of the S-enantiomer after multiple dosing (i.e. under steady-state conditions). This may be because of higher concentrations of R-citalopram at steady state. The biological half-life of R-citalopram is longer than escitalopram, because its metabolism and elimination from the body is slower than that of escitalopram. In the studies by Klein et al. (2006, 2007), the ratio of R-enantiomer to S-enantiomer in serum 6 h after dosing with 20 mg citalopram was 1.16 after a single dose and 1.6 after multiple dosing, increasing to 2.9 at 54 h (Fig. 3).
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[Email Jumpstart To Image] Fig. 2 Dynamics of midbrain serotonin reuptake transporter (SERT) occupancy after single dosing and multiple dosing (i.e., under steady-state conditions) for escitalopram (a) and citalopram (b). For escitalopram, single doses were 5 mg (n = 5), 10 mg (n = 5) and 20 mg (n = 5); multiple doses were 10 mg/day only (n = 9). For citalopram, single doses were 10 mg (n = 5) and 20 mg (n = 5); multiple doses were 20 mg/day only (n = 6) (Klein et al., 2006, 2007). Significantly (P<0.05) higher SERT occupancy was observed with escitalopram compared with citalopram after multiple dosing, that is, under steady-state conditions.Graphic
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[Email Jumpstart To Image] Fig. 3 Plasma pharmacokinetics of the R-enantiomer and S-enantiomer of citalopram after single (20 mg) and multiple dosing (20 mg/day for 10 days) of citalopram. (a) The ratio of the R-enantiomer to S-enantiomer increases between single dose and steady state (after multiple dosing): ratios are 1.16 : 1 (6 h after single dosing), 1.6 : 1 (6 h after multiple dosing) and 2.9 : 1 (54 h after multiple dosing). (b) A higher elimination half-life is observed for the R-enantiomer versus S-enantiomer of citalopram, as measured 6 h after multiple dosing (data from Klein et al., 2006, 2007).The finding that SERT occupancy is restricted by the R-enantiomer after multiple, but not single, dosing is of functional and clinical importance. Higher occupancy by escitalopram is likely to be associated with more complete SERT inhibition and further potentiation of serotonergic output (Mork et al., 2003). Significant reductions in the serotonin-enhancing and mood-altering effects of escitalopram in the presence of R-citalopram have been consistently reported in a number of in-vitro and preclinical in-vivo experiments (Mork et al., 2003; Sanchez and Kreilgaard, 2004; Storustovu et al., 2004). The studies by Klein et al. (2006, 2007) provide indirect evidence for fractional binding of the supposedly inactive R-enantiomer to the SERT. These data are supported by those of Mansari et al. (2007), who showed that R-citalopram counteracted the activity of S-citalopram in vitro by acting at an allosteric binding site on the SERT to attenuate the association of [3H]escitalopram at the high-affinity site with an EC50 value of 94±18 nmol/l. 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 54h timepoints in the multiple-dose 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. In a study in 22 patients with MDD who received 40 mg/day citalopram, after 4 weeks the concentration of escitalopram in cerebrospinal fluid (CSF) was approximately half that of R-citalopram (10.6±4.3 vs. 20.9±6 ng/ml), with corresponding CSF/plasma ratios of 52±9 and 48±6% for R-citalopram and escitalopram, respectively. Thus, the concentrations of both enantiomers in CSF are approximately half those found in plasma (Nikisch et al., 2004).
Despite the fact that escitalopram has a higher affinity for SERT than does R-citalopram (Chen et al., 2005), the higher relative concentration of R-citalopram may allow it to more readily displace escitalopram from the allosteric binding site (Mansari et al., 2007). The interaction between R-citalopram and escitalopram (two SERT antagonists with different potencies) seems to be a unique phenomenon. Kinetic analysis suggests that S-citalopram binding to SERT induces a long-lasting, inhibited state of the transporter and R-citalopram partially relieves SERT of this persistent inhibition (Storustovu et al., 2004). Previously reported functional antagonism between enantiomers of other drugs involve interactions between one agonist enantiomer and another antagonist enantiomer (Brauner-Osborne et al., 1996; Sanchez et al., 2004). Moreover, in-vitro binding studies show that R-citalopram, at clinically relevant concentrations, attenuates the association rates of escitalopram and paroxetine to the 5-HT transporter, but has no effect on the association rates of fluoxetine, venlafaxine or sertraline (Mansari et al., 2007).
It is possible that the R-enantiomer induces different conformational changes in SERTs than are seen with the S-enantiomer; for example, the long-lasting inhibition of SERT by escitalopram may be the result of phosphorylation, homo/hetero-oligomerization or ligand-induced internalization. Transporter phosphorylation and sequestration of SERTs are highly regulated by a complex combination of protein kinase and phosphatase pathways (Ramamoorthy et al., 1998; Ramamoorthy and Blakely, 1999). Some studies have shown that antidepressants that are nontransported 5-HT inhibitors can block substrate-induced upregulation of SERT and related transporter activity (Ramamoorthy and Blakely, 1999; Whitworth et al., 2002).
Our SPECT studies have some limitations that have to be taken into account when interpreting their findings. Both studies investigated only healthy men and sample sizes were rather small, both issues which narrow the generalizability of the results. The ability of escitalopram and citalopram to penetrate the brain and accumulate around the synapses and axons was not assessed; differences in capacity of cerebral penetration of these substances might account for a certain amount of variability. The hypothesis that a receptor occupancy of 80% is necessary for a therapeutic effect (Meyer et al., 2004) is based on [11C]DASB PET studies, in contrast to the [123I]ADAM SPECT studies presented here. Obviously, PET and SPECT imaging differ in resolution and the ligands differ in their specificity for SERT. Both ligands show highly selective binding towards and high binding affinity for SERT. However, in rodent studies, DASB seems to have a higher ratio of specific versus nonspecific binding than ADAM (Choi et al., 2000; Wilson et al., 2000). Beyond this lower signal-to-noise ratio in ADAM compared with DASB, there are several challenges in SERT quantification using [123I]ADAM. The time of peak-specific [123I]ADAM binding is highly variable among volunteers (Booij and de Win, 2006), and there are discrepancies between tissue ratio-derived binding parameters and kinetic modelling-derived parameters in quantification (Frokjaer et al., 2008; Slifstein, 2008). In contrast to SPECT studies (Kugaya et al., 2004; Herold et al., 2006), several PET studies with [11C]DASB failed to show a significant association between SERT occupancy and treatment response (Meyer, 2007) indicating relevant differences in affinity to the SERT-binding site. Further research into the molecular mechanisms by which antidepressants regulate SERTs is required.
ConclusionClinical studies have consistently reported that escitalopram is more effective than citalopram in the treatment of depression. The most probable reason for the lower efficacy with citalopram is the attenuation, by the supposedly inactive R-citalopram, of the S-enantiomer of citalopram (the active enantiomer) binding to an allosteric site on the SERT. The extent to which R-citalopram inhibits the S-enantiomer occupancy of SERT is greater with multiple dosing, because of the slower metabolism and elimination of R-citalopram, thereby reducing the effectiveness of escitalopram at the primary SERT-binding site. These post-hoc pooled analysis, together with the results of the studies by Klein et al. (2006, 2007) provide additional evidence to support the putative time-dependent physiological mechanisms by which escitalopram achieves superior clinical effectiveness over citalopram.
AcknowledgementsThe authors thank Natalie Barker of Wolters Kluwer Health for providing writing assistance for this manuscript (funded by H. Lundbeck A/S).
Conflicts of interest: S. Kasper received grants/research support, consulting fees and honoraria within the last 3 years from AstraZeneca, Bristol-Myers Squibb, CSC, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutica, Lundbeck, MSD, Novartis, Organon, Pierre Fabre, Pfizer, Schwabe, Sepracor, Servier, Wyeth; R. Lanzenberger received a travel grant, research support and conference speaker honoraria from Lundbeck; C. Spindelegger received a travel grant from Lundbeck; J. Sacher, N. Klein, N. Mossaheb, T. Attarbaschi-Steiner, S. Asenbaum, A. Holik and R. Dudczak have no conflicts of interest in the context of the subject of this article.
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Keywords: chiral switching; citalopram; escitalopram; major depressive disorder; selective serotonin reuptake inhibitors; serotonin reuptake transporter occupancy; serotonin transporters
Posted by sdb on May 3, 2009, at 14:29:52
In reply to Lexapro more effective than Celexa - Why?, posted by SLS on May 2, 2009, at 10:58:41
is it really more effective practically or is it only a question of a dosage equivalence from biochemical theory aside ...?
Posted by SLS on May 3, 2009, at 20:12:10
In reply to Re: Lexapro more effective than Celexa - Why?, posted by sdb on May 3, 2009, at 14:29:52
> is it really more effective practically or is it only a question of a dosage equivalence from biochemical theory aside ...?
I think most clinicians have found that Lexapro is more effective than Celexa at all dosages. The study that you provided here (thanks) indicates that once Celexa reaches a steady-state, the R-citalopram enantiomer collects and reaches a greater concentration than the S-citalopram enantiomer, thereby disrupting the therapeutic effect of S-citalopram.
- Scott
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