Escitalopram versus citalopram: the surprising role of the R-enantiomer

Abstract

Rationale

Citalopram is a racemate consisting 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 citalopram to placebo found that equivalent doses of these two drugs, i.e. containing the same amount of the S-enantiomer, 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 neurochemical, functional, and behavioural non-clinical experiments, 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 citalopram counteracts the activity of the S-enantiomer, thereby providing a possible basis for the pharmacological and clinical differences observed between citalopram and escitalopram.

Appendices

Appendix 1: Rodent behavioural models for testing the action of antidepressant and anxiolytic drugs

Animal models are commonly used both to screen new compounds for antidepressant and anxiolytic activity, and to study the mechanism of action of established drugs. As disorders such as depression are so uniquely human, it is best to consider such models as simulating particular symptoms, rather than modelling an entire diagnostic entity. Nonetheless, the models described below have been shown to be sensitive and selective, to varying degrees, in identifying drugs with clinical usefulness in the treatment of depression and anxiety (see description and cited references for each model). For a general review of the validity and reliability of such models see Willner (1991) and Cryan et al. (2002).

Chronic mild stress (CMS)

This model is highly predictive of SSRI antidepressant activity (Willner 1997). Rats are sequentially exposed to a variety of mild stressors for a period of several weeks. As with stressed or depressed people, stressed rats exhibit behavioural hedonic deficits, measured in the CMS model as decreased consumption of a freely available sugar solution (Willner 1997). The ability of drugs to return sugar consumption to normal levels is tested.

Resident-intruder model

A male rat housed alone tends to attack any newly introduced cage mates. The suppression of this aggressive behaviour is highly predictive of the action of antidepressant drugs (Willner 1991).

Forced swim test

Based on reversal of swim-induced immobility, this model is predictive of antidepressant activity (Borsini 1995). Mice are placed for 6 min in a 2-l Pyrex beaker half filled with water; the duration of which the mouse remains immobile is assessed during the final 3 min.

Ultrasonic vocalisation (USV)

This model, which mimics aspects of panic anxiety, is predictive of anxiolytic activity (e.g. Sánchez 2003b). A short series of foot shocks induces USV in rats. This response is inhibited by pretreatment with SSRIs.

Black and white two-compartment box

Rodents avoid open, brightly lit areas, which inhibit their natural tendency to explore novel environments. In this model, which is used to test anxiolytic activity, the rat or mouse is placed in an apparatus comprising dark and brightly lit areas connected by an opening. Time spent in exploratory activity in each compartment is measured. Benzodiazepines are reliably detected in this model, 5-HT_1A agonists are generally detected, while the response to SSRIs is more variable (see, e.g. Hascoët et al. 2001).

Conditioned fear

A model of anxiety (Borsini et al. 2002) based on the conditioned suppression of exploratory behaviour in rats by association with a previously experienced aversive stimulus, e.g. mild electric foot shocks. Treatment with benzodiazepines and serotonergic anxiolytics prior to re-exposure has consistently been found to counteract this behavioural suppression.

Appendix 2: Stereochemistry of chiral antidepressant drugs

SSRIs

Citalopram has one chiral centre. The S-enantiomer, escitalopram, is a far more potent inhibitor of serotonin reuptake than R-citalopram (see main text for details). In patients treated with citalopram, the steady-state level of escitalopram in plasma is generally lower than that of R-citalopram (Sidhu et al. 1997).

Escitalopram is the active enantiomer in citalopram (see main text for details).

Fluoxetine (FLX) has one chiral centre and is a racemate. S-FLX and R-FLX are almost equally potent serotonin reuptake inhibitors (Wong et al. 1995), but the metabolite S-norFLX is also a potent serotonin reuptake inhibitor, while R-norFLX is about 20 times weaker (Wong et al. 1993a). S-FLX and S-norFLX are the predominant enantiomers present in plasma at steady state (Lane and Baker 1999), and S-FLX inhibits CYP2D6 more than R-FLX does (Stevens and Wrighton 1993). For these reasons, R-FLX was chosen for development as a single enantiomer drug but development was abandoned due to potential cardiotoxicity resulting from prolongation of the QTc interval (DeVane 2002).

Paroxetine has two chiral centres and was launched as the 3S,4R-enantiomer because this trans-enantiomer has about 130 times greater serotonin reuptake inhibition than 3R,4S-paroxetine (Plenge et al. 1987). The cis-enantiomers are weak inhibitors of serotonin reuptake (Plenge et al. 1987).

Sertraline has two chiral centres but was launched as the 1S,4S-enantiomer because the 1R,4R-enantiomer possesses potent dopamine reuptake inhibition activity in addition to moderate serotonin reuptake inhibition (Welch 1995). 1S,4S-sertraline has about 10 times greater serotonin reuptake inhibition than 1R,4R-sertraline (Welch et al. 1984; Welch 1995).

Tetracyclics

Mianserin (MIA) has one chiral centre. Plasma levels of S-MIA are generally higher than those of R-MIA (Eap et al. 1995). Furthermore, S-MIA is more potent in behavioural models predictive of antidepressant activity (Hand et al. 1991), and in noradrenaline reuptake inhibition and in blockade of presynaptic α₂-receptors (Pinder and Van-Delft 1983). However, the therapeutic efficacy of MIA may be due to the activities of both its enantiomers: S-MIA has greater affinity for 5-HT_1A, 5-HT_1B, 5-HT_1C, and 5-HT₂ receptors (Hand et al. 1991), while R-MIA binds 30 times more strongly to 5-HT₃ receptors (Wood et al. 1993).

Mirtazapine (MIR) has one chiral centre. (+)-MIR is 37 times more potent in inhibiting α₂-autoreceptors, while (−)-MIR is 140 times more potent in inhibiting 5-HT₃ receptors (de Boer et al. 1995). The pharmacokinetics of MIR appears to be stereoselective (Delbressine et al. 1998), and there is differential metabolism of the enantiomers of MIR by cytochrome P450 enzymes in vitro (Dodd et al. 2001), but the clinical significance of these differences is unknown. Like mianserin, the pharmacological properties of both enantiomers of MIR appear to be important for the activity of the racemate (Kooyman et al. 1994; McGrath et al. 1998).

NRIs

Reboxetine has two chiral centres and is a mixture of the R,R-enantiomers and S,S-enantiomers; S,S-reboxetine is more potent in antidepressant tests (Frigerio et al. 1994), consistent with its 24-fold greater potency in inhibiting noradrenalin reuptake (Strolin et al. 1995).

Viloxazine has one chiral centre. A variety of in vitro and in vivo measures have established that S-viloxazine is about 50 times more potent as an NRI (Blackburn et al. 1978), and at least 5 times more potent as an antidepressant (Howe et al. 1976; Danchev et al. 1984) than R-viloxazine.

SNRIs

Duloxetine has one chiral centre and the S-enantiomer is currently being tested in phase III clinical trials (Berglund 1994). This enantiomer was chosen due to its slightly higher serotonin reuptake inhibitory effect (Wong et al. 1993b).

Milnacipran is a racemate. Both enantiomers have been shown to be active (Deprez et al. 1998).

Venlafaxine (VLF) has one chiral centre. S-VLF has SSRI-like activity with a ratio of serotonin to noradrenaline reuptake inhibition of 31 based on IC₅₀ values, while R-VLF has an activity ratio of about 4 (Yardley et al. 1990). As a result, the racemate has a selectivity profile that leads to reuptake inhibition of the two neurotransmitters. The major metabolite in humans, o-desmethyl VLF, has monoamine reuptake inhibitory properties similar to the parent compound (Muth et al. 1986).