Psychopharmacology (2004) 174: 163–176 DOI 10.1007/s00213-004-1865-z REVIEW Connie Sánchez . Klaus P. Bøgesø . Bjarke Ebert . Elin Heldbo Reines . Claus Braestrup Escitalopram versus citalopram: the surprising role of the R-enantiomer Received: 25 September 2003 / Accepted: 26 February 2004 / Published online: 25 May 2004 # Springer-Verlag 2004 Abstract Rationale: Citalopram is a racemate consist- ing of a 1:1 mixture of the R(-)- and S(+)-enantiomers. Non-clinical studies show that the serotonin reuptake inhibitory activity of citalopram is attributable to the S- 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 the S-enanti- omer, showed better effect for escitalopram. These results suggested that the R-citalopram in citalopram inhibits the effect of the S-enantiomer. Objective: To review the pharmacological and non-clinical literature that describes the inhibition of escitalopram by R-citalopram, as well as the implications of this inhibition for the clinical efficacy of escitalopram compared 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 the S-enantiomer by the R-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: The R-enantiomer present in citalo- pram counteracts the activity of the S-enantiomer, thereby providing a possible basis for the pharmacological and clinical differences observed between citalopram and escitalopram. Keywords Escitalopram . Citalopram . R-citalopram . Enantiomers . Stereochemistry . SSRI . Serotonin transporter . Depression . Panic disorder . Antidepressant Introduction The selective serotonin reuptake inhibitor (SSRI) citalo- pram is a racemate that comprises an S(+)-enantiomer (escitalopram) and an R(-)-enantiomer (R-citalopram) in a 1:1 ratio (Fig. 1). In studies using the individual enantiomers, the S-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 Sánchez 1999) 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 Tucker 2000; Agranat et al. 2002 for a review of enantiomers and “chiral switches”). 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 the S- enantiomer. Subsequent studies have provided a possible pharmacological explanation for an effect difference between citalopram and escitalopram by demonstrating that the R-enantiomer in citalopram counteracts the activity of the S-enantiomer in vitro and in vivo (e.g. Mørk et al. 2003). This review summarises the data regarding the inhibition of the effect of escitalopram by R- citalopram, and suggests that the better clinical effect observed for escitalopram versus citalopram is due to the removal of this inhibition. C. Sánchez . K. P. Bøgesø . B. Ebert . E. H. Reines . C. Braestrup Research and Development, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby Copenhagen, Denmark C. Sánchez (*) Neuropharmacological Research, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby Copenhagen, Denmark e-mail: cs@lundbeck.com Tel.: +45-36432517 Fax: +45-36432832