Escitalopram versus citalopram: the surprising role of the R-enantiomer
- 1.4k Downloads
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.
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.
The information in this review was gathered from published articles and abstracts.
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.
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.
KeywordsEscitalopram Citalopram R-citalopram Enantiomers Stereochemistry SSRI Serotonin transporter Depression Panic disorder Antidepressant
The authors acknowledge Yaron Y. Levy for assistance in preparing the manuscript.
- Berglund RA (1994) Asymmetric synthesis. US Patent 5362886, 8 Nov 1994, p 3Google Scholar
- Bien E, Gruca P, Papp M (2003) R-Citalopram attenuates the anxiolytic-like activity of escitalopram in two animal models. Behav Pharmacol 14:S37Google Scholar
- de Boer T, Ruigt GSF, Berendsen HHG (1995) The (α2-selective adrenoreceptor antagonist org 3770 (mirtazapine, Remeron) enhances noradrenergic and serotonergic transmission. Hum Psychopharmacol Clin Exp 10(Suppl 2):107–118Google Scholar
- Borsini F, Podhorna J, Marazziti D (2002) Do animal models of anxiety predict anxiolytic-like effects of antidepressants? Psychopharmacology 163:121–141Google Scholar
- Burke WJ (2001) Fixed dose study of escitalopram in the treatment of depression. Abstract and poster 518 presented at the annual meeting of the American Psychiatric Association, May 5–10, 2001, New OrleansGoogle Scholar
- Colonna L, Reines EH, Andersen HF (2002) Escitalopram is well tolerated and more efficacious than citalopram in long-term treatment of moderately depressed patients. Int J Psychol Clin Prac 6:243–244Google Scholar
- Cremers TIFH, Westerink BHC (2003) Pharmacological difference between escitalopram and citalopram. Int J Psychiatr Clin Prac 7:306Google Scholar
- Danchev ND, Rozhanets VV, Zhmurenko LA, Glozman OM, Zagoreversuskii VA, Valdman AV (1984) Byulleten Eksperimental’noi Biologii I Meditsiny 97:576–578Google Scholar
- Delbressine LPC, Moonen MEG, Kaspersen FM, Wagenaars GN, Jacobs PL, Timmer CJ, Paanakker JE, Van Hal HJM, Voortman G (1998) Pharmacokinetics and biotransformation of mirtazapine in human volunteers. Clin Drug Invest 15:45–55Google Scholar
- DeVane CL (2002) Refining current therapies: clinical implications to the treatment of depression. Molecules and mood disorders: drug discovery and the treatment of depression. Program and abstracts of the American Psychiatric Association 155th annual meeting, May 18–23 2002, Philadelphia, Pa.Google Scholar
- Eap CB, Powell K, Campussouche D, Monney C, Baettig D, Taeschner W, Baumann P (1995) Determination of the enantiomers of mianserin, desmethylmianserin, and 8-hydroxymianserin in the plasma and urine of mianserin-treated patients. Chirality 6:555–563Google Scholar
- Ebert B, Lenz S, Brehm L, Bregnedal P, Hansen JJ, Frederiksen K, Bøgesø KP, Krogsgaard-Larsen P (1994) Resolution, absolute stereochemistry, and pharmacology of the S-(+)- and R-(−)-isomers of the apparent partial AMPA receptor agonist (R,S)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid [(R,S)-APPA]. J Med Chem 37:878–884PubMedGoogle Scholar
- Frigerio E, Pianezzola E, Strolin Benedetti M (1994) Sensitive procedure for the determination of reboxetine enantiomers in human plasma by reversed phase HPLC with fluorimetric detection after chiral derivatization with (+)-1-(9-fluorenyl)ethyl chloroformate. J Chromatogr A 660:351–358CrossRefPubMedGoogle Scholar
- Gumnick JF, Nemeroff CB (2000) Problems with currently available antidepressants. J Clin Psychiatry 61(Suppl 10):5–15Google Scholar
- Guy W (1976) ECDEU assessment manual for psychopharmacology (rev. 1976) Biometric Laboratory. The George Washington University, Kensington, Md. US Department of Health, Education, and Welfare, DHEW publication no. (ADM) 218–222Google Scholar
- Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62Google Scholar
- Hyttel J, Bøgesø KP, Perregaard J, Sánchez C (1992) The pharmacological effect of citalopram resides in the (S)-(+)-enantiomer. J Neural Transm [Gen Sect] 88:157–160Google Scholar
- Lepola U, Wade W, Andersen HF (2004) Do equivalent doses of escitalopram and citalopram have similar efficacy?—a pooled analysis of two positive placebo-controlled studies in major depressive disorder. Int Clin Psychopharmacol (in press)Google Scholar
- Lucki I, Brown K (2003) Different roles of the enantiomers of citalopram on serotonin transmission. Biol Psychiatry 53:45SGoogle Scholar
- Mitchell PJ, Hogg S (2001) Behavioural effects of escitalopram predict potent antidepressant activity. Biol Psychiatry 49:115SGoogle Scholar
- Mitchell PJ, Hogg S (2002) Effects of escitalopram (S-(+)-citalopram) in the resident-intruder model of antidepressant drug activity. J Psychopharmacol 16:A42Google Scholar
- Owens MJ, Knight DL, Nemeroff CB (2001) Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry 50:345–350Google Scholar
- Sánchez C, Bergqvist PBF, Brennum LT, Gupta S, Hogg S, Larsen A, Wiborg O (2003a) Escitalopram, the S-(+)-enantiomer of citalopram, is a selective serotonin reuptake inhibitor with potent effects in animal models predictive of antidepressant and anxiolytic activities. Psychopharmacology 167:353–362PubMedGoogle Scholar
- Stevens JC, Wrighton SA (1993) Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. J Pharmacol Exp Ther 266:964–971Google Scholar
- Stórustovu S, Sánchez C, Pörzgen P, Brennum LT, Larsen AK, Pulis M, Ebert B (2004) R-Citalopram functionally antagonizes escitalopram in vivo and in vitro: evidence for kinetic interaction at the serotonin transporter. Br J Pharmacol (in press)Google Scholar
- Welch WM (1995) Discovery and preclinical development of the serotonin reuptake inhibitor sertraline. In: Maryanoff BE, Maryanoff CA (eds) Advances of medicinal chemistry. JAI, London, pp 113–148Google Scholar
- Willner P (1997) Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology 134:319–329Google Scholar