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Science and pharmacy

Do not assume equality

From Mrs C. L. Feetam, MRPharmS

Timothy Snape and Alison Astles’s Article on fundamental chemical principles was long overdue in serving to remind pharmacists of the science that underpins our profession (PJ, 10 July 2010, p59).

As an example, they describe the chirality of citalopram and subsequent development of escitalopram, a similar antidepressant with twice the potency.

What is even more interesting is that the 5-hydroxytryptamine-elevating effect of escitalopram in animal brain microdialysis studies was always more than twice that of citalopram and even high doses of citalopram could not match the maximal effects of escitalopram.1,2

In addition, when the R-enantiomer was added to escitalopram, it reduced its elevating effect on 5-HT in both behavioural and biochemical assays.3

These preclinical studies clearly suggest escitalopram has effects greater than predicted from simply having twice the potency of citalopram, and it appears that R-citalopram has some negative impact on the 5-HT reuptake inhibitory effect of escitalopram.

R-citalopram has much lower affinity for the reuptake site on the 5-HT transporter than escitalopram. However, there appears to be another binding site on the 5-HT transporter that binds both escitalopram and R-citalopram — the so-called allosteric site.4–6

When this is occupied by escitalopram, the effect of its binding to the traditional transporter reuptake site is enhanced and prolonged. R-citalopram, although it does not bind to the reuptake site, does bind to the allosteric site and, in doing so, displaces escitalopram, reducing its ability to enhance its own action allosterically at the reuptake site and lessening the effect of escitalopram on 5-HT reuptake.6

These unwanted actions of R-citalopram counteract the anxiolytic effects of escitalopram.7 They also attenuate the 5-HT reuptake inhibitory effect of escitalopram and explain why escitalopram has a faster onset of action than citalopram in rodent models of depression.8

In overdose, escitalopram appears to be less toxic than citalopram.9,10 This supports the hypothesis that R-citalopram is not biologically inert and that escitalopram may also have safety advantages over citalopram.

The authors stated that the intention of the article was to demonstrate the close link between the science of chemistry and pharmacy practice. The clinical implications of the stereochemistry of ciltalopram are that it is inappropriate to switch a patient who is doing well from escitalopram to citalopram on the basis of cost or formulary exclusion.

Such substitution of an alternative selective serotonin reuptake inhibitor has been shown to incur additional costs.11

Our knowledge of chemistry should tell us that equality between enantiomers and racemic mixtures cannot be assumed.

Celia Feetam

Clinical Psychiatric Pharmacist

Department of Psychiatry Pharmacy

Aston University



1    Mørk A, Kreilgaard M, Sánchez C. The R-enantiomer of citalopram counteracts escitalopram-induced increase in extracellular 5-HT in the frontal cortex of freely moving rats. Neuropharmacology 2003;45:167-73.

2    Sánchez C, Kreilgaard M. R-citalopram inhibits functional and 5-HTP-evoked behavioural responses to the SSRI, escitalopram. Pharmacology Biochemistry and Behaviour 2004;77:391-8.

3    Stórustovu S, Sánchez C, Pörzgen P, Brennum LT, Larsen AK, Pulis M et al. R-citalopram functionally antagonises escitalopram in vivo and in vitro: evidence for kinetic interaction at the serotonin transporter. Journal of Pharmacology 2004;142:172-80.

4    Chen F, Larsen MB, Sánchez C, Wiborg O. The S-enantiomer of R, S-citalopram, increases inhibitor binding to the human serotonin transporter by an allosteric mechanism. Comparison with other serotonin transporter inhibitors. European Neuropsychopharmacology 2005;15:193-8.

5    Chen F, Larsen MB, Neubauer HA, Sánchez C, Plenge P, Wiborg O. Characterisation of an allosteric citalopram-binding site at the serotonin transporter. Journal of Neurochemistry 2005;92:21-8.

6    Plenge P, Gether U, Rasmussen SG (2007) Allosteric effects of R- and S-citalopram on the human 5-HT transporter: evidence for distinct high- and low-affinity binding sites. European Journal of Pharmacology 2007;567:1-9.

7    Sánchez C, Gruca P, Bien E, Papp M. R-citalopram counteracts the effect of escitalopram in a rat conditioned fear stress model of anxiety Pharmacology, Biochemistry and Behaviour. 2003;75:903-7.

8    Sánchez C, Gruca P, Papp M. R-citalopram counteracts the antidepressant-like effect of escitalopram in a rat chronic mild stress model. Behavioural Pharmacology.2003;14:465-70.

9    Hayes BD, Klein-Schwartz W, Clark RF, Muller AA, Miloradovich JE. Comparison of toxicity of acute overdoses with citalopram and escitalopram. Journal of Emergency Medicine 2010;39:44-8.

10    Yilmaz Z, Ceschi A, Rauber-Lüthy C, Sauer O, Stedtler U, Prasa D et al. Escitalopram causes fewer seizures in human overdose than citalopram. Clinical Toxicology (Philadelphia, Pa.). 2010;48:207-12.

11    Wu EQ, Ben-Hamadi R, Yu AP, Tang J, Haim Erder M, Bose A. Healthcare utilisation and costs incurred by patients with major depression after being switched from escitalopram to another SSRI for non-medical reasons. Journal of Medical Economics 2010;13:314-23.

Mrs Feetam receives honorary and consultancy fees from Lundbeck, which manufactures escitalopram. — EDITOR

Citation: The Pharmaceutical Journal URI: 11021603

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