Psychopharmacology

, Volume 174, Issue 2, pp 163–176 | Cite as

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

  • Connie Sánchez
  • Klaus P. Bøgesø
  • Bjarke Ebert
  • Elin Heldbo Reines
  • Claus Braestrup
Review

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.

Keywords

Escitalopram Citalopram R-citalopram Enantiomers Stereochemistry SSRI Serotonin transporter Depression Panic disorder Antidepressant 

Notes

Acknowledgements

The authors acknowledge Yaron Y. Levy for assistance in preparing the manuscript.

References

  1. Agranat I, Caner H, Caldwell J (2002) Putting chirality to work: the strategy of chiral switches. Nat Rev Drug Discov 1:753–768CrossRefPubMedGoogle Scholar
  2. Allan AM, Harris RA (1986) Anesthetic and convulsant barbiturates alter gamma-aminobutyric acid-stimulated chloride flux across brain membranes. J Pharmacol Exp Ther 238:763–768PubMedGoogle Scholar
  3. Attenburrow MJ, Mitter PR, Whale R, Terao T, Cowen PJ (2001) Low-dose citalopram as a 5-HT neuroendocrine probe. Psychopharmacology 155:323–326PubMedGoogle Scholar
  4. Auquier P, Robitail S, Llorca P-M, Rive B (2003) Comparison of escitalopram and citalopram efficacy: a meta-analysis. Int J Psychiatr Clin Pract 7:259–268CrossRefGoogle Scholar
  5. Berglund RA (1994) Asymmetric synthesis. US Patent 5362886, 8 Nov 1994, p 3Google Scholar
  6. 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
  7. Blackburn TP, Foster GA, Greenwood DT, Howe R (1978) Effects of viloxazine, its optical isomers and its major metabolites on biogenic amine uptake mechanisms in vitro and in vivo. Eur J Pharmacol 52:367–374CrossRefPubMedGoogle Scholar
  8. 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
  9. Boja JW, Mitchell WM, Patel A, Kopajtic TA, Carroll FI, Lewin AH, Abraham P, Kuhar MJ (1992) High-affinity binding of [125I]RTI-55 to dopamine and serotonin transporters in rat brain. Synapse 12:27–36PubMedGoogle Scholar
  10. Borsini F (1995) Role of the serotonergic system in the forced swimming test. Neurosci Biobehav Rev 19:377–395PubMedGoogle Scholar
  11. Borsini F, Podhorna J, Marazziti D (2002) Do animal models of anxiety predict anxiolytic-like effects of antidepressants? Psychopharmacology 163:121–141Google Scholar
  12. Brøsen K, Naranjo CA (2001) Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram. Eur Neuropsychopharmacol 11:275–283CrossRefPubMedGoogle Scholar
  13. 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
  14. Burke WJ, Gergel I, Bose A (2002) Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry 63:331–336PubMedGoogle Scholar
  15. Carter RB, Dykstra LA (1984) Quantitative analysis of the interaction between the agonist and antagonist isomers of picenadol (LY150720) on electric shock titration in the squirrel monkey. Eur J Pharmacol 106:469–476CrossRefPubMedGoogle Scholar
  16. Chen F, Larsen MB, Sánchez C, Wiborg O (2003) The S-enantiomer of citalopram increases inhibitor binding to the human serotonin transporter by an allosteric mechanism. Comparison with other serotonin transporter inhibitors. Eur Neuropsychopharmacol 13:S217CrossRefGoogle Scholar
  17. 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
  18. Cremers TIFH, Westerink BHC (2003) Pharmacological difference between escitalopram and citalopram. Int J Psychiatr Clin Prac 7:306Google Scholar
  19. Cryan JF, Markou A, Lucki I (2002) Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 23:238–245CrossRefPubMedGoogle Scholar
  20. Danchev ND, Rozhanets VV, Zhmurenko LA, Glozman OM, Zagoreversuskii VA, Valdman AV (1984) Byulleten Eksperimental’noi Biologii I Meditsiny 97:576–578Google Scholar
  21. 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
  22. Deprez D, Chassard D, Baille P, Mignot A, Ung HL, Puozzo C (1998) Which bioequivalence study for a racemic drug? Application to milnacipran. Eur J Drug Metab Pharmacokinet 23:166–171PubMedGoogle Scholar
  23. 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
  24. Dodd S, Boulton DW, Burrows GD, DeVane CL, Norman TR (2001) In vitro metabolism of mirtazapine enantiomers by human cytochrome P450 enzymes. Hum Psychopharmacol 16:541–544CrossRefPubMedGoogle Scholar
  25. 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
  26. 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
  27. Fish EW, Faccidomo S, Gupta S, Miczek KA (2004) Anxiolytic-like effects of escitalopram, citalopram and R-citalopram in maternally separated mouse pups. J Pharmacol Exp Ther 308:474–480CrossRefPubMedGoogle Scholar
  28. Foglia JP, Pollock BG, Kirshner MA, Rosen J, Sweet R, Mulsant B (1997) Plasma levels of citalopram enantiomers and metabolites in elderly patients. Psychopharmacol Bull 33:109–112PubMedGoogle Scholar
  29. 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
  30. Fuller RW, Perry KW, Hemrick-Luecke SK, Engleman E (1996) Serum corticosterone increases reflect enhanced uptake inhibitor-induced elevation of extracellular 5-hydroxytryptamine in rat hypothalamus. J Pharm Pharmacol 48:68–70PubMedGoogle Scholar
  31. Gumnick JF, Nemeroff CB (2000) Problems with currently available antidepressants. J Clin Psychiatry 61(Suppl 10):5–15Google Scholar
  32. 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
  33. Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62Google Scholar
  34. Hand TH, Marek GJ, Seiden LS (1991) Comparison of the effects of mianserin and its enantiomers and metabolites on a behavioral screen for antidepressant activity. Psychopharmacology 105:453–458PubMedGoogle Scholar
  35. Hascoët M, Bourin M, Dhonnchadha BAN (2001) The mouse light-dark paradigm: a review. Prog Neuropsychopharmacol Biol Psychiatry 25:141–166PubMedGoogle Scholar
  36. Hogg S, Sánchez C (1999) The antidepressant effects of citalopram are mediated by the S-(+)- and not the R-(−)-enantiomer. Eur Neuropsychopharmacol 9(Suppl 1):S213CrossRefGoogle Scholar
  37. Howe R, Leigh T, Rao BS, Todd AH (1976) Optical isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4-oxazine (viloxazine) and related compounds. J Med Chem 19:1074–1076PubMedGoogle Scholar
  38. 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
  39. Jørgensen H, Knigge U, Kjaer A, Warberg J (1996) Interactions of histaminergic and serotonergic neurons in the hypothalamic regulation of prolactin and ACTH secretion. Neuroendocrinology 64:329–336PubMedGoogle Scholar
  40. Keller MB (2000) Citalopram therapy for depression: a review of 10 years of European experience and data from US clinical trials. J Clin Psychiatry 61:896–908PubMedGoogle Scholar
  41. Kooyman AR, Zwart R, Vanderheijden PML, van Hooft JA, Vijverberg HPM (1994) Interaction between enantiomers of mianserin and ORG3770 at 5-HT3 receptors in cultured mouse neuroblastoma cells. Neuropharmacology 33:501–507CrossRefPubMedGoogle Scholar
  42. Lane RM, Baker GB (1999) Chirality and drugs used in psychiatry: nice to know or need to know? Cell Mol Neurobiol 19:355–372CrossRefPubMedGoogle Scholar
  43. Larsen AK, Brennum LT, Egebjerg J, Sánchez C, Halldin C, Andersen PH (2004) Selectivity of 3H-MADAM binding to 5-hydroxytryptamine transporters in vitro and in vivo in mice; correlation with behavioural effects. Br J Pharmacol 141:1015–1023CrossRefPubMedGoogle Scholar
  44. Leander JD, Hart JC, Lochner MA, Hynes MD III, Zimmerman DM (1982) Novel phenylpiperidine opioid antagonists and partial agonists: effects on fluid consumption. Eur J Pharmacol 81:185–192CrossRefPubMedGoogle Scholar
  45. Lepola UM, Loft H, Reines EH (2003) Escitalopram (10–20 mg/day) is effective and well tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol 18:211–217CrossRefPubMedGoogle Scholar
  46. 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
  47. Lin EH, Von-Korff M, Katon W, Bush T, Simon GE, Walker E, Robinson P (1995) The role of the primary care physician in patients’ adherence to antidepressant therapy. Med Care 33:67–74PubMedGoogle Scholar
  48. Lucki I, Brown K (2003) Different roles of the enantiomers of citalopram on serotonin transmission. Biol Psychiatry 53:45SGoogle Scholar
  49. McGrath C, Burrows GD, Norman TR (1998) Neurochemical effects of the enantiomers of mirtazapine in normal rats. Eur J Pharmacol 356:121–126CrossRefPubMedGoogle Scholar
  50. Meyer J, Wilson A, Ginovart N, Goulding V, Hussey D, Hood K et al. (2001) Occupancy of serotonin transporters by paroxetine and citalopram during treatment of depression: a [11C]DASB PET imaging study. Am J Psychiatry 158:1843–1849PubMedGoogle Scholar
  51. Mitchell PJ, Hogg S (2001) Behavioural effects of escitalopram predict potent antidepressant activity. Biol Psychiatry 49:115SGoogle Scholar
  52. Mitchell PJ, Hogg S (2002) Effects of escitalopram (S-(+)-citalopram) in the resident-intruder model of antidepressant drug activity. J Psychopharmacol 16:A42Google Scholar
  53. Montgomery SA, Åsberg M (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382–389PubMedGoogle Scholar
  54. Montgomery SA, Loft H, Sánchez C, Reines EH, Papp M (2001) Escitalopram (S-enantiomer of citalopram): clinical efficacy and onset of action predicted from a rat model. Pharmacol Toxicol 88:282–286PubMedGoogle Scholar
  55. Mørk A, Kreilgaard M, Sánchez C (2003) The R-enantiomer of citalopram counteracts escitalopram-induced increase in extracellular 5-HT in the frontal cortex of freely moving rats. Neuropharmacology 45:167–173CrossRefPubMedGoogle Scholar
  56. Muth EA, Haskins JT, Moyer JA et al (1986) Antidepressant biochemical profile of the novel bicyclic compound Wy-45,030, an ethyl cyclohexanol derivative. Biochem Pharmacol 35:4493–4497PubMedGoogle Scholar
  57. 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
  58. Pinder RM, Van-Delft AM (1983) The potential therapeutic role of the enantiomers and metabolites of mianserin. Br J Clin Pharmacol 15:269S–276SPubMedGoogle Scholar
  59. Plenge P, Mellerup ET (1985) Antidepressive drugs can change the affinity of [3H]imipramine and [3H]paroxetine binding to platelet and neuronal membranes. Eur J Pharmacol 119:1–8PubMedGoogle Scholar
  60. Plenge P, Mellerup ET, Honoré T, le Fèvre Honoré P (1987) The activity of 25 paroxetine/femoxetine structure variants in various reactions, assumed to be important for the effect of antidepressants. J Pharm Pharmacol 39:877–882PubMedGoogle Scholar
  61. Plenge P, Mellerup ET, Laursen H (1991) Affinity modulation of [3H]imipramine, [3H]paroxetine and [3H]citalopram binding to the 5-HT transporter from brain and platelets. Eur J Pharmacol 206:243–250PubMedGoogle Scholar
  62. Raap DK, Van de Kar LD (1999) Selective serotonin reuptake inhibitors and neuroendocrine function. Life Sci 65:1217–1235PubMedGoogle Scholar
  63. Rochat B, Baumann P, Audus KL (1999) Transport mechanisms for the antidepressant citalopram in brain microvessel endothelium. Brain Res 831:229–236PubMedGoogle Scholar
  64. Sánchez C (2003a) R-citalopram attenuates anxiolytic effects of escitalopram in a rat ultrasonic vocalisation model. Eur J Pharmacol 464:155–158CrossRefPubMedGoogle Scholar
  65. Sánchez C (2003b) Stress-induced vocalisation in adult animals. A valid model of anxiety? Eur J Pharmacol 463:133–143CrossRefPubMedGoogle Scholar
  66. Sánchez C, Hyttel J (1994) Isolation-induced aggression in mice: effects of 5-hydroxytryptamine uptake inhibitors and involvement of postsynaptic 5-HT1A receptors. Eur J Pharmacol 264:241–247PubMedGoogle Scholar
  67. Sánchez C, Kreilgaard M (2004) R-citalopram inhibits functional and 5-HTP-evoked behavioural responses to the SSRI, escitalopram. Pharmacol Biochem Behav 77:391–398CrossRefPubMedGoogle Scholar
  68. 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
  69. Sánchez C, Gruca P, Bien E, Papp M (2003b) R-citalopram counteracts the effect of escitalopram in a rat conditioned fear stress model of anxiety. Pharmacol Biochem Behav 75:903–907CrossRefPubMedGoogle Scholar
  70. Sánchez C, Gruca P, Papp M (2003c) R-citalopram counteracts the antidepressant-like effect of escitalopram in a rat chronic mild stress model. Behav Pharmacol 14:465–470PubMedGoogle Scholar
  71. Sidhu J, Priskorn M, Poulsen M, Segonzac A, Grollier G, Larsen F (1997) Steady-state pharmacokinetics of the enantiomers of citalopram and its metabolites in humans. Chirality 9:686–692CrossRefPubMedGoogle Scholar
  72. Stahl S, Gergel I, Li D (2003) Escitalopram in the treatment of panic disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 64:1322–1327PubMedGoogle Scholar
  73. 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
  74. 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
  75. Strolin B, Frigerio E, Tocchetti P, Brianceschi G, Castelli MG, Pellizzoni C, Dostert P (1995) Stereoselective and species-dependent kinetics of reboxetine in mouse and rat. Chirality 7:285–289PubMedGoogle Scholar
  76. Ticku MK, Rastogi SK, Thyagarajan R (1985) Separate site(s) of action of optical isomers of 1-methyl-5-phenyl-5-propylbarbituric acid with opposite pharmacological activities at the GABA receptor complex. Eur J Pharmacol 112:1–9CrossRefPubMedGoogle Scholar
  77. Tucker GT (2000) Chiral switches. Lancet 355:1085–1087CrossRefPubMedGoogle Scholar
  78. 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
  79. Welch WM, Kraska AR, Sarges R, Koe B K (1984) Nontricyclic antidepressant agents derived from cis- and trans-1-amino-4-aryltetralins. J Med Chem 27:1508–1515PubMedGoogle Scholar
  80. Wennogle LP, Meyerson LR (1985) Serotonin uptake inhibitors differentially modulate high affinity imipramine dissociation in human platelet membranes. Life Sci 36:1541–1550CrossRefPubMedGoogle Scholar
  81. Wiborg O, Sánchez C (2003) R-citalopram decreases the association of [3H]-S-citalopram with the human serotonin transporter by an allosteric mechanism. Eur Neuropsychopharmacol 13:S217CrossRefGoogle Scholar
  82. Willner P (1991) Animal models as simulations of depression. Trends Pharmacol Sci 12:131–136PubMedGoogle Scholar
  83. 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
  84. Wong DT, Bymaster FP, Ried LR, Mayle DA, Krushinski JH, Robertson DW (1993a) Norfluoxetine enantiomers as inhibitors of serotonin uptake in rat brain. Neuropsychopharmacology 8:337–344PubMedGoogle Scholar
  85. Wong DT, Bymaster FP, Mayle DA, Reid LR, Krushinski JH, Robertson DW (1993b) LY248686, a new inhibitor of serotonin and norepinephrine uptake. Neuropsychopharmacology 8:23–33PubMedGoogle Scholar
  86. Wong DT, Bymaster FP, Engleman EA (1995) Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: twenty years since its first publication. Life Sci 57:411–441PubMedGoogle Scholar
  87. Wood MD, Thomas DR, Watkins CJ, Newberry NR (1993) Stereoselective interaction of mianserin with 5-HT3 receptors. J Pharm Pharmacol 45:711–714PubMedGoogle Scholar
  88. Yardley JP, Morris-Husbands GE, Stack G, Butch J, Bicksler J, Moyer JA, Muth EA, Andree T, Fletcher H III, James MNG, Sielecki AR (1990) 2-Phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives: synthesis and antidepressant activity. J Med Chem 33:2899–2905PubMedGoogle Scholar
  89. Zheng Z, Jamour M, Klotz U (2000) Stereoselective HPLC-assay for citalopram and its metabolites. Ther Drug Monit 22:219–224CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Connie Sánchez
    • 1
    • 2
  • Klaus P. Bøgesø
    • 1
  • Bjarke Ebert
    • 1
  • Elin Heldbo Reines
    • 1
  • Claus Braestrup
    • 1
  1. 1.Research and DevelopmentH. Lundbeck A/SValby CopenhagenDenmark
  2. 2.Neuropharmacological ResearchH. Lundbeck A/SValby CopenhagenDenmark

Personalised recommendations