ing of a 1:1 mixture of theR(\u2212)- andS(+)-enantiomers. Non-clinical studies show that the serotonin reuptake inhibitory activity of citalopram is attributable to theS- enantiomer, escitalopram. A series of recent non-clinical and clinical studies comparing escitalopram and citalo- pram to placebo found that equivalent doses of these two drugs, i.e. containing the same amount of theS-enanti- omer, showed better effect for escitalopram. These results suggested that theR-citalopram in citalopram inhibits the effect of theS-enantiomer.Objective: To review the pharmacological and non-clinical literature that describes the inhibition of escitalopram byR-citalopram, as well as the implications of this inhibition for the clinical efficacy of escitalopramcompared to citalopram.Methods: The information in this review was gathered from published articles and abstracts.Results: In appropriate neuro- chemical, functional, and behavioural non-clinical experi- ments, escitalopram shows greater efficacy and faster onset of action than comparable doses of citalopram. The lower efficacy of citalopram in these studies is apparently due to the inhibition of the effect of theS-enantiomer by theR-enantiomer, possibly via an allosteric interaction with the serotonin transporter. Data from randomised clinical trials consistently show better efficacy with escitalopram than with citalopram, including higher rates of response and remission, and faster time to symptom relief.Conclusion: TheR-enantiomer present in citalo- pramcounteracts the activity of theS-enantiomer, thereby

providing a possible basis for the pharmacological and clinical differences observed between citalopram and escitalopram.

The selective serotonin reuptake inhibitor (SSRI) citalo- pram is a racemate that comprises anS(+)-enantiomer (escitalopram) and anR(\u2212)-enantiomer (R-citalopram) in a 1:1 ratio (Fig.1). In studies using the individual enantiomers, theS-enantiomer has been shown to be responsible for essentially all the serotonin reuptake inhibition (Hyttel et al.1992) and non-clinical antidepres- sant activity (Hogg and S\u00e1nchez1999) of citalopram. These observations provided the impetus to develop escitalopram as an antidepressant in its own right, and in 2002 escitalopram was launched as a new single-enanti- omer drug (see Tucker2000; Agranat et al.2002 for a review of enantiomers and\u201cchiral switches\u201d).

A clinical study in patients with major depressive disorder (MDD), and a non-clinical study using a rat behavioural model of depression both found that the onset of effect of escitalopram versus placebo was faster than citalopram versus placebo (Montgomery et al.2001). This result was surprising because the animals and patients in these two studies received equivalent amounts of theS- enantiomer. Subsequent studies have provided a possible pharmacological explanation for an effect difference between citalopram and escitalopram by demonstrating that theR-enantiomer in citalopram counteracts the activity of theS-enantiomer in vitro and in vivo (e.g. M\u00f8rk et al.2003). This review summarises the data regarding the inhibition of the effect of escitalopram byR- citalopram, and suggests that the better clinical effect observed for escitalopram versus citalopram is due to the removal of this inhibition.

C. S\u00e1nchez. K. P. B\u00f8ges\u00f8. B. Ebert. E. H. Reines.
C. Braestrup
Research and Development, H. Lundbeck A/S,
Ottiliavej 9,
2500 Valby Copenhagen, Denmark

Neuropharmacological Research, H. Lundbeck A/S,
Ottiliavej 9,
2500 Valby Copenhagen, Denmark
e-mail: cs@lundbeck.com
Tel.: +45-36432517
Fax: +45-36432832

The effects of the enantiomers of citalopram have been investigated using a variety of in vitro and in vivo measures (summarised in Table1). In terms of serotonin reuptake inhibitor activity,R-citalopram was about 150 times less potent than escitalopram in an in vitro rat brain synaptosome system (Hyttel et al.1992; S\u00e1nchez et al.

expressing the human serotonin transporter protein (Owens et al.2001; S\u00e1nchez et al.2003a) confirmed that as an inhibitor of transporter activity escitalopram is about twice as potent as citalopram, and at least 27-fold more potent thanR-citalopram (Table1). Each enantiomer also had markedly different effects on the binding of ligands to the transporter, e.g. [125I]-RTI-55 (2-\u03b2-carbomethoxy-3\u03b2- (4-iodophenyl)tropane; a cocaine analogue used as a high- affinity probe of the serotonin transporter (Boja et al.

aResults on different measures are based on IC50, ED50,Ki, or MED values as indicated
bHyttel et al. (1992)
cS\u00e1nchez et al. (2003a)
dOwens et al. (2001)
eRecalculated from\u03bcmol/kg
fS\u00e1nchez and Hyttel (1994)
gMitchell and Hogg (2001)

In vivo, the effect of acute administration of citalopram, escitalopram, andR-citalopram was evaluated by poten- tiation of 5-hydroxytryptophan (a serotonin precursor) in rodents (Hyttel et al.1992), and by inhibition of the neuronal firing rate in the rat dorsal raphe nucleus (S\u00e1nchez et al.2003a) (Table1). In accordance with the measurements of in vitro reuptake inhibition, escitalopram was approximately twice as potent as citalopram in eliciting a given functional or behavioural response in rodents, andR-citalopram was much less potent (Table1). The results of these biochemical and functional experi- ments are consistent with the original concept of citalopram as a 1:1 mixture of therapeutically active (escitalopram) and essentially inactive (R-citalopram) enantiomers. Therefore, based solely on the amount of

clinical trials evaluating the effect of escitalopram and citalopram a given dose of escitalopram would be equivalent to twice the dose of citalopram (Owens et al.

The first evidence to suggest that equivalent doses of escitalopram and citalopram may not be the same in terms of effect came fromtwo early studies, one non-clinical and one clinical (Montgomery et al.2001). In the non-clinical study, the activity of escitalopram and citalopram was tested relative to placebo using the rat chronic mild stress model, which is predictive of antidepressant activity (see Appendix1). Two different daily doses of escitalopram (3.9 and 7.8 mg base/kg) and one of citalopram (8 mg base/kg) were shown to be effective compared with vehicle (placebo) in normalising the hedonic deficit in stressed rats, but while both escitalopram doses achieved this effect within 1 week of administration, citalopram required 2 weeks (Montgomery et al.2001). Furthermore, at week 1 the effect of 3.9 mg/kg escitalopram was significantly different from 8 mg/kg citalopram (P<0.05; S\u00e1nchez, unpublished data) (Fig.2). Faster onset of action for escitalopramthan for citalopram has subsequently been confirmed in another chronic mild stress study (S\u00e1nchez et al.2003c) and in the rat resident-intruder model (Mitchell and Hogg2002), where escitalopram required 1 day to reach statistically significantly separation from vehicle- treated controls, while citalopram first separated after 4 days of treatment.

In the randomised, double-blind clinical study reported by Montgomery et al. (2001), patients with MDD (baseline Montgomery-\u00c5sberg Depression Rating Scale [MADRS; Montgomery and \u00c5sberg1979] score between 22 and 40), received flexible doses of 10\u201320 mg escitalopram (n=155), 20\u201340 mg citalopram (n=160), or placebo (n=154) once daily for 8 weeks, with lowest dose fixed for the first 4 weeks. In an analysis of the fixed-dose period, both escitalopram and citalopram improved the

mean change from baseline in MADRS total score compared to placebo, but escitalopram was statistically significantly superior to placebo from week 1 and onwards, while citalopram was not statistically signifi- cantly different from placebo before week 6. Using data fromthe entire 8-week study period, escitalopram resulted in greater improvement than citalopram at all time points on all three efficacy scales used in the study [MADRS, Clinical Global Impressions-Improvement, and Clinical Global Impressions-Severity (CGI-I and CGI-S; Guy

non-clinical studies reported in Montgomery et al. (2001) were notable because a given dose of escitalopramdid not result in the same effect as twice as much citalopram, suggesting that theR-enantiomer, while inactive in terms of SSRI activity, may limit the effect of theS-enantiomer.

Data supporting the view that theR-enantiomer inhibits the effect of theS-enantiomer first came from neurochem- ical experiments in which various acute doses of citalopram, escitalopram, andR-citalopram were adminis- tered to rats and the levels of extracellular serotonin in the frontal cortex were monitored by microdialysis (M\u00f8rk et al.2003). Surprisingly, when 2 mg/kg escitalopram was compared to 4 mg/kg citalopram, escitalopram elicited an increase in brain serotonin levels that was about twice that with citalopram (Fig.3a). When escitalopram was administered together with twice or 4 times as muchR- citalopram, theR-enantiomer significantly inhibited theS- enantiomer-induced increase in serotonin level in a dose- dependent manner (Fig.3a) (M\u00f8rk et al.2003). These ratios of R/S enantiomers are clinically relevant because, in humans, the two enantiomers have different rates of clearance resulting in a steady-stateR/S ratio of about 2:1 in the serum of subjects treated with citalopram (Foglia et al.1997; Sidhu et al.1997; Zheng et al.2000; Br\u00f8sen and

pram in chronic mild stressed rats. The mean (+SE) change in sucrose intake in grams (g) between week 0 and week 1 in chronic mild stressed rats administered either 8 mg/kg citalopram or 3.9 mg/ kg escitalopram is shown (S\u00e1nchez, unpublished data). There was a statistically significant difference (P=0.032,t-test) between the treatments. Neither escitalopram nor citalopram affected sucrose intake in unstressed controls