Psychopharmacology

, Volume 219, Issue 1, pp 1–13 | Cite as

Escitalopram, an antidepressant with an allosteric effect at the serotonin transporter—a review of current understanding of its mechanism of action

Review

Abstract

Rationale

Escitalopram is a widely used antidepressant for the treatment of patients with major depression. It is the pure S-enantiomer of racemic citalopram. Several clinical trials and meta-analyses indicate that escitalopram is quantitatively more efficacious than many other antidepressants with a faster onset of action.

Objective

This paper reviews current knowledge about the mechanism of action of escitalopram.

Results

The primary target for escitalopram is the serotonin transporter (SERT), which is responsible for serotonin (or 5-hydroxytryptamine [5-HT]) reuptake at the terminals and cell bodies of serotonergic neurons. Escitalopram and selective serotonin reuptake inhibitors bind with high affinity to the 5-HT binding site (orthosteric site) on the transporter. This leads to antidepressant effects by increasing extracellular 5-HT levels which enhance 5-HT neurotransmission. SERT also has one or more allosteric sites, binding to which modulates activity at the orthosteric binding site but does not directly affect 5-HT reuptake by the transporter. In vitro studies have shown that through allosteric binding, escitalopram decreases its own dissociation rate from the orthosteric site on the SERT. R-citalopram, the nontherapeutic enantiomer in citalopram, is also an allosteric modulator of SERT but can inhibit the actions of escitalopram by interfering negatively with its binding. Both nonclinical studies and some clinical investigations have demonstrated the cellular, neurochemical, neuroadaptive, and neuroplastic changes induced by escitalopram with acute and chronic administration.

Conclusions

The findings from binding, neurochemical, and neurophysiological studies may provide a mechanistic rationale for the clinical difference observed with escitalopram compared to other antidepressant therapies.

Keywords

Escitalopram (S-citalopram) Allosteric Serotonin (5-HT) Serotonin transporter (SERT) Selective serotonin reuptake inhibitor (SSRI) 

References

  1. Alboni S, Benatti C, Capone G, Corsini D, Caggia F, Tascedda F, Mendlewicz J, Brunello N (2010) Time-dependent effects of escitalopram on brain derived neurotrophic factor (BDNF) and neuroplasticity related targets in the central nervous system of rats. Eur J Pharmacol 643:180–187PubMedCrossRefGoogle Scholar
  2. Ali MK, Lam RW (2011) Comparative efficacy of escitalopram in the treatment of major depressive disorder. Neuropsychiatr Dis Treat 7:39–49PubMedGoogle Scholar
  3. Andersen J, Taboureau O, Hansen KB, Olsen L, Egebjerg J, Stromgaard K, Kristensen AS (2009) Location of the antidepressant binding site in the serotonin transporter: importance of Ser-438 in recognition of citalopram and tricyclic antidepressants. J Biol Chem 284:10276–10284PubMedCrossRefGoogle Scholar
  4. Aydemir C, Yalcin ES, Aksaray S, Kisa C, Yildirim SG, Uzbay T, Goka E (2006) Brain-derived neurotrophic factor (BDNF) changes in the serum of depressed women. Prog Neuropsychopharmacol Biol Psychiatry 30:1256–1260PubMedCrossRefGoogle Scholar
  5. Balu DT, Hoshaw BA, Malberg JE, Rosenzweig-Lipson S, Schechter LE, Lucki I (2008) Differential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments. Brain Res 1211:37–43PubMedCrossRefGoogle Scholar
  6. Banasr M, Duman RS (2007) Regulation of neurogenesis and gliogenesis by stress and antidepressant treatment. CNS Neurol Disord Drug Targets 6:311–320PubMedCrossRefGoogle Scholar
  7. Barbiero VS, Giambelli R, Musazzi L, Tiraboschi E, Tardito D, Perez J, Drago F, Racagni G, Popoli M (2007) Chronic antidepressants induce redistribution and differential activation of alphaCaM kinase II between presynaptic compartments. Neuropsychopharmacology 32:2511–2519PubMedCrossRefGoogle Scholar
  8. Bech P, Tanghoj P, Cialdella P, Andersen HF, Pedersen AG (2004) Escitalopram dose–response revisited: an alternative psychometric approach to evaluate clinical effects of escitalopram compared to citalopram and placebo in patients with major depression. Int J Neuropsychopharmacol 7:283–290PubMedCrossRefGoogle Scholar
  9. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47:351–354PubMedCrossRefGoogle Scholar
  10. Bhagya V, Srikumar BN, Raju TR, Shankaranarayana Rao BS (2011) Chronic escitalopram treatment restores spatial learning, monoamine levels, and hippocampal long-term potentiation in an animal model of depression. Psychopharmacology (Berl) 214:477–494CrossRefGoogle Scholar
  11. Blakely RD, De Felice LJ, Hartzell HC (1994) Molecular physiology of norepinephrine and serotonin transporters. J Exp Biol 196:263–281PubMedGoogle Scholar
  12. Blakely RD, Ramamoorthy S, Schroeter S, Qian Y, Apparsundaram S, Galli A, DeFelice LJ (1998) Regulated phosphorylation and trafficking of antidepressant-sensitive serotonin transporter proteins. Biol Psychiatry 44:169–178PubMedCrossRefGoogle Scholar
  13. Blier P, de Montigny C (1999) Serotonin and drug-induced therapeutic responses in major depression, obsessive-compulsive and panic disorders. Neuropsychopharmacology 21:91S–98SPubMedGoogle Scholar
  14. Boos TL, Greiner E, Calhoun WJ, Prisinzano TE, Nightingale B, Dersch CM, Rothman RB, Jacobson AE, Rice KC (2006) Structure–activity relationships of substituted N-benzyl piperidines in the GBR series: synthesis of 4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(2-trifluoromethylbenzyl)piperidine, an allosteric modulator of the serotonin transporter. Bioorg Med Chem 14:3967–3973PubMedCrossRefGoogle Scholar
  15. Celik L, Sinning S, Severinsen K, Hansen CG, Moller MS, Bols M, Wiborg O, Schiott B (2008) Binding of serotonin to the human serotonin transporter. Molecular modeling and experimental validation. J Am Chem Soc 130:3853–3865PubMedCrossRefGoogle Scholar
  16. Chanrion B, la Mannoury CC, Bertaso F, Lerner-Natoli M, Freissmuth M, Millan MJ, Bockaert J, Marin P (2007) Physical interaction between the serotonin transporter and neuronal nitric oxide synthase underlies reciprocal modulation of their activity. Proc Natl Acad Sci U S A 104:8119–8124PubMedCrossRefGoogle Scholar
  17. Chen F, Larsen MB, Neubauer HA, Sanchez C, Plenge P, Wiborg O (2005a) Characterization of an allosteric citalopram-binding site at the serotonin transporter. J Neurochem 92:21–28PubMedCrossRefGoogle Scholar
  18. Chen F, Larsen MB, Sanchez C, Wiborg O (2005b) 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. Eur Neuropsychopharmacol 15:193–198PubMedCrossRefGoogle Scholar
  19. Cipriani A, Santilli C, Furukawa TA, Signoretti A, Nakagawa A, McGuire H, Churchill R, Barbui C (2009) Escitalopram versus other antidepressive agents for depression. Cochrane Database Syst Rev 2:CD006532PubMedGoogle Scholar
  20. Di Mascio M, Di Giovanni G, Di Matteo V, Prisco S, Esposito E (1998) Selective serotonin reuptake inhibitors reduce the spontaneous activity of dopaminergic neurons in the ventral tegmental area. Brain Res Bull 46:547–554PubMedCrossRefGoogle Scholar
  21. Donati RJ, Dwivedi Y, Roberts RC, Conley RR, Pandey GN, Rasenick MM (2008) Postmortem brain tissue of depressed suicides reveals increased Gs alpha localization in lipid raft domains where it is less likely to activate adenylyl cyclase. J Neurosci 28:3042–3050PubMedCrossRefGoogle Scholar
  22. Dremencov E, El Mansari M, Blier P (2009) Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area. J Psychiatry Neurosci 34:223–229PubMedGoogle Scholar
  23. Drevets WC, Thase ME, Moses-Kolko EL, Price J, Frank E, Kupfer DJ, Mathis C (2007) Serotonin-1A receptor imaging in recurrent depression: replication and literature review. Nucl Med Biol 34:865–877PubMedCrossRefGoogle Scholar
  24. El Mansari M, Sanchez C, Chouvet G, Renaud B, Haddjeri N (2005) Effects of acute and long-term administration of escitalopram and citalopram on serotonin neurotransmission: an in vivo electrophysiological study in rat brain. Neuropsychopharmacology 30:1269–1277PubMedGoogle Scholar
  25. El Mansari M, Wiborg O, Mnie-Filali O, Benturquia N, Sanchez C, Haddjeri N (2007) Allosteric modulation of the effect of escitalopram, paroxetine and fluoxetine: in-vitro and in-vivo studies. Int J Neuropsychopharmacol 10:31–40CrossRefGoogle Scholar
  26. Glatt CE, DeYoung JA, Delgado S, Service SK, Giacomini KM, Edwards RH, Risch N, Freimer NB (2001) Screening a large reference sample to identify very low frequency sequence variants: comparisons between two genes. Nat Genet 27:435–438PubMedCrossRefGoogle Scholar
  27. Hahn A, Lanzenberger R, Wadsak W, Spindelegger C, Moser U, Mien LK, Mitterhauser M, Kasper S (2010) Escitalopram enhances the association of serotonin-1A autoreceptors to heteroreceptors in anxiety disorders. J Neurosci 30:14482–14489PubMedCrossRefGoogle Scholar
  28. Henry LK, Field JR, Adkins EM, Parnas ML, Vaughan RA, Zou MF, Newman AH, Blakely RD (2006) Tyr-95 and Ile-172 in transmembrane segments 1 and 3 of human serotonin transporters interact to establish high affinity recognition of antidepressants. J Biol Chem 281:2012–2023PubMedCrossRefGoogle Scholar
  29. Jacobsen JP, Mork A (2004) The effect of escitalopram, desipramine, electroconvulsive seizures and lithium on brain-derived neurotrophic factor mRNA and protein expression in the rat brain and the correlation to 5-HT and 5-HIAA levels. Brain Res 1024:183–192PubMedCrossRefGoogle Scholar
  30. Jayatissa MN, Bisgaard C, Tingstrom A, Papp M, Wiborg O (2006) Hippocampal cytogenesis correlates to escitalopram-mediated recovery in a chronic mild stress rat model of depression. Neuropsychopharmacology 31:2395–2404PubMedCrossRefGoogle Scholar
  31. Jorgensen AM, Topiol S (2008) Driving forces for ligand migration in the leucine transporter. Chem Biol Drug Des 72:265–272PubMedCrossRefGoogle Scholar
  32. Kasper S, Spadone C, Verpillat P, Angst J (2006) Onset of action of escitalopram compared with other antidepressants: results of a pooled analysis. Int Clin Psychopharmacol 21:105–110PubMedCrossRefGoogle Scholar
  33. Kasper S, Baldwin DS, Larsson LS, Boulenger JP (2009a) Superiority of escitalopram to paroxetine in the treatment of depression. Eur Neuropsychopharmacol 19:229–237PubMedCrossRefGoogle Scholar
  34. Kasper S, Sacher J, Klein N, Mossaheb N, Attarbaschi-Steiner T, Lanzenberger R, Spindelegger C, Asenbaum S, Holik A, Dudczak R (2009b) Differences in the dynamics of serotonin reuptake transporter occupancy may explain superior clinical efficacy of escitalopram versus citalopram. Int Clin Psychopharmacol 24:119–125PubMedCrossRefGoogle Scholar
  35. Kennedy SH, Andersen HF, Thase ME (2009) Escitalopram in the treatment of major depressive disorder: a meta-analysis. Curr Med Res Opin 25:161–175PubMedCrossRefGoogle Scholar
  36. Kilic F, Murphy DL, Rudnick G (2003) A human serotonin transporter mutation causes constitutive activation of transport activity. Mol Pharmacol 64:440–446PubMedCrossRefGoogle Scholar
  37. Koldso H, Severinsen K, Tran TT, Celik L, Jensen HH, Wiborg O, Schiott B, Sinning S (2010) The two enantiomers of citalopram bind to the human serotonin transporter in reversed orientations. J Am Chem Soc 132:1311–1322PubMedCrossRefGoogle Scholar
  38. Kornstein SG, Li D, Mao Y, Larsson S, Andersen HF, Papakostas GI (2009) Escitalopram versus SNRI antidepressants in the acute treatment of major depressive disorder: integrative analysis of four double-blind, randomized clinical trials. CNS Spectr 14:326–333PubMedGoogle Scholar
  39. Kreilgaard M, Smith DG, Brennum LT, Sanchez C (2008) Prediction of clinical response based on pharmacokinetic/pharmacodynamic models of 5-hydroxytryptamine reuptake inhibitors in mice. Br J Pharmacol 155:276–284PubMedCrossRefGoogle Scholar
  40. Lam RW, Lonn SL, Despiegel N (2010) Escitalopram versus serotonin noradrenaline reuptake inhibitors as second step treatment for patients with major depressive disorder: a pooled analysis. Int Clin Psychopharmacol 25:199–203PubMedCrossRefGoogle Scholar
  41. Leonard B, Taylor D (2010) Escitalopram—translating molecular properties into clinical benefit: reviewing the evidence in major depression. J Psychopharmacol 24:1143–1152PubMedCrossRefGoogle Scholar
  42. Lepola U, Wade A, 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 19:149–155PubMedCrossRefGoogle Scholar
  43. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531PubMedCrossRefGoogle Scholar
  44. Leuchter AF, Cook IA, Gilmer WS, Marangell LB, Burgoyne KS, Howland RH, Trivedi MH, Zisook S, Jain R, Fava M, Iosifescu D, Greenwald S (2009a) Effectiveness of a quantitative electroencephalographic biomarker for predicting differential response or remission with escitalopram and bupropion in major depressive disorder. Psychiatry Res 169:132–138PubMedCrossRefGoogle Scholar
  45. Leuchter AF, Cook IA, Marangell LB, Gilmer WS, Burgoyne KS, Howland RH, Trivedi MH, Zisook S, Jain R, McCracken JT, Fava M, Iosifescu D, Greenwald S (2009b) Comparative effectiveness of biomarkers and clinical indicators for predicting outcomes of SSRI treatment in major depressive disorder: results of the BRITE-MD study. Psychiatry Res 169:124–131PubMedCrossRefGoogle Scholar
  46. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329:959–964PubMedCrossRefGoogle Scholar
  47. Loland CJ, Plenge P, Shi L, Zhang P, Javitch JA, Newman AH, Weinstein H, Gether U (2010) Mapping of the allosteric binding site in the serotonin transporter. Basic Clin Pharmacol Toxicol 107:116–117Google Scholar
  48. Lotrich FE, Pollock BG (2004) Meta-analysis of serotonin transporter polymorphisms and affective disorders. Psychiatr Genet 14:121–129PubMedCrossRefGoogle Scholar
  49. Lucassen PJ, Meerlo P, Naylor AS, van Dam AM, Dayer AG, Fuchs E, Oomen CA, Czeh B (2010) Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: implications for depression and antidepressant action. Eur Neuropsychopharmacol 20:1–17PubMedCrossRefGoogle Scholar
  50. McHugh RK, Hofmann SG, Asnaani A, Sawyer AT, Otto MW (2010) The serotonin transporter gene and risk for alcohol dependence: a meta-analytic review. Drug Alcohol Depend 108:1–6PubMedCrossRefGoogle Scholar
  51. Millan MJ (2006) Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Ther 110:135–370PubMedCrossRefGoogle Scholar
  52. Mnie-Filali O, Faure C, El Mansari M, Lambas-Senas L, Berod A, Zimmer L, Sanchez C, Haddjeri N (2007) R-citalopram prevents the neuronal adaptive changes induced by escitalopram. Neuroreport 18:1553–1556PubMedCrossRefGoogle Scholar
  53. Mnie-Filali O, El Mansari M, Sanchez C, Haddjeri N (2009) R-citalopram prevents the neuronal adaptive changes induced by escitalopram. Curr Sign Trans Ther 4:82–87CrossRefGoogle Scholar
  54. Montgomery SA, Moller HJ (2009) Is the significant superiority of escitalopram compared with other antidepressants clinically relevant? Int Clin Psychopharmacol 24:111–118PubMedCrossRefGoogle Scholar
  55. Montgomery SA, Baldwin DS, Blier P, Fineberg NA, Kasper S, Lader M, Lam RW, Lepine JP, Moller HJ, Nutt DJ, Rouillon F, Schatzberg AF, Thase ME (2007) Which antidepressants have demonstrated superior efficacy? A review of the evidence. Int Clin Psychopharmacol 22:323–329PubMedCrossRefGoogle Scholar
  56. Montgomery S, Hansen T, Kasper S (2011) Efficacy of escitalopram compared to citalopram: a meta-analysis. Int J Neuropsychopharmacol 14:261–268PubMedCrossRefGoogle Scholar
  57. Mork A, Kreilgaard M, Sanchez C (2003) The R-enantiomer of citalopram counteracts escitalopram-induced increase in extracellular 5-HT in the frontal cortex of freely moving rats. Neuropharmacology 45:167–173PubMedCrossRefGoogle Scholar
  58. Morphy R, Rankovic Z (2009) Designing multiple ligands—medicinal chemistry strategies and challenges. Curr Pharm Des 15:587–600PubMedCrossRefGoogle Scholar
  59. Muhonen LH, Lahti J, Alho H, Lonnqvist J, Haukka J, Saarikoski ST (2011) Serotonin transporter polymorphism as a predictor for escitalopram treatment of major depressive disorder comorbid with alcohol dependence. Psychiatry Res 186(1):53–57PubMedCrossRefGoogle Scholar
  60. Musazzi L, Mallei A, Tardito D, Gruber SH, El KA, Racagni G, Mathe AA, Popoli M (2010) Early-life stress and antidepressant treatment involve synaptic signaling and Erk kinases in a gene-environment model of depression. J Psychiatr Res 44:511–520PubMedCrossRefGoogle Scholar
  61. Nandi A, Dersch CM, Kulshrestha M, Ananthan S, Rothman RB (2004) Identification and characterization of a novel allosteric modulator (SoRI-6238) of the serotonin transporter. Synapse 53:176–183PubMedCrossRefGoogle Scholar
  62. Nellissery M, Feinn RS, Covault J, Gelernter J, Anton RF, Pettinati H, Moak D, Mueller T, Kranzler HR (2003) Alleles of a functional serotonin transporter promoter polymorphism are associated with major depression in alcoholics. Alcohol Clin Exp Res 27:1402–1408PubMedCrossRefGoogle Scholar
  63. Neubauer HA, Hansen CG, Wiborg O (2006) Dissection of an allosteric mechanism on the serotonin transporter: a cross-species study. Mol Pharmacol 69:1242–1250PubMedCrossRefGoogle Scholar
  64. Nightingale B, Dersch CM, Boos TL, Greiner E, Calhoun WJ, Jacobson AE, Rice KC, Rothman RB (2005) Studies of the biogenic amine transporters. XI. Identification of a 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR12909) analog that allosterically modulates the serotonin transporter. J Pharmacol Exp Ther 314:906–915PubMedCrossRefGoogle Scholar
  65. Nikisch G, Mathe AA, Czernik A, Eap CB, Jimenez-Vasquez P, Brawand-Amey M, Baumann P (2004) Stereoselective metabolism of citalopram in plasma and cerebrospinal fluid of depressive patients: relationship with 5-HIAA in CSF and clinical response. J Clin Psychopharmacol 24:283–290PubMedCrossRefGoogle Scholar
  66. Nutt DJ, Feetam CL (2010) What one hand giveth the other taketh away: some unpredicted effects of enantiomers in psychopharmacology. J Psychopharmacol 24:1137–1141PubMedCrossRefGoogle Scholar
  67. Owens MJ (2007) C.20.01 new pharmacological tools in evaluation of antidepressant molecules. Eur Neuropsychopharmacol 17:S610CrossRefGoogle Scholar
  68. Owens MJ, Nemeroff CB (1994) Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 40:288–295PubMedGoogle Scholar
  69. Ozaki N, Goldman D, Kaye WH, Plotnicov K, Greenberg BD, Lappalainen J, Rudnick G, Murphy DL (2003) Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype. Mol Psychiatry 8:933–936PubMedCrossRefGoogle Scholar
  70. Peng Q, Masuda N, Jiang M, Li Q, Zhao M, Ross CA, Duan W (2008) The antidepressant sertraline improves the phenotype, promotes neurogenesis and increases BDNF levels in the R6/2 Huntington’s disease mouse model. Exp Neurol 210:154–163PubMedCrossRefGoogle Scholar
  71. Plenge P, Mellerup ET (1997) An affinity-modulating site on neuronal monoamine transport proteins. Pharmacol Toxicol 80:197–201PubMedCrossRefGoogle Scholar
  72. Plenge P, Wiborg O (2005) High- and low-affinity binding of S-citalopram to the human serotonin transporter mutated at 20 putatively important amino acid positions. Neurosci Lett 383:203–208PubMedCrossRefGoogle Scholar
  73. 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. Eur J Pharmacol 567:1–9PubMedCrossRefGoogle Scholar
  74. Prasad HC, Zhu CB, McCauley JL, Samuvel DJ, Ramamoorthy S, Shelton RC, Hewlett WA, Sutcliffe JS, Blakely RD (2005) Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase. Proc Natl Acad Sci U S A 102:11545–11550PubMedCrossRefGoogle Scholar
  75. Prisco S, Esposito E (1995) Differential effects of acute and chronic fluoxetine administration on the spontaneous activity of dopaminergic neurones in the ventral tegmental area. Br J Pharmacol 116:1923–1931PubMedGoogle Scholar
  76. Racagni G, Popoli M (2008) Cellular and molecular mechanisms in the long-term action of antidepressants. Dialogues Clin Neurosci 10:385–400PubMedGoogle Scholar
  77. Rao N (2007) The clinical pharmacokinetics of escitalopram. Clin Pharmacokinet 46:281–290PubMedCrossRefGoogle Scholar
  78. Rochat B, Kosel M, Boss G, Testa B, Gillet M, Baumann P (1998) Stereoselective biotransformation of the selective serotonin reuptake inhibitor citalopram and its demethylated metabolites by monoamine oxidases in human liver. Biochem Pharmacol 56:15–23PubMedCrossRefGoogle Scholar
  79. Ryan B, Musazzi L, Mallei A, Tardito D, Gruber SH, El KA, Anwyl R, Racagni G, Mathe AA, Rowan MJ, Popoli M (2009) Remodelling by early-life stress of NMDA receptor-dependent synaptic plasticity in a gene-environment rat model of depression. Int J Neuropsychopharmacol 12:553–559PubMedCrossRefGoogle Scholar
  80. Sanchez C (2006) The pharmacology of citalopram enantiomers: the antagonism by R-citalopram on the effect of S-citalopram. Basic Clin Pharmacol Toxicol 99:91–95PubMedCrossRefGoogle Scholar
  81. Sanchez C, Kreilgaard M (2004) R-citalopram inhibits functional and 5-HTP-evoked behavioural responses to the SSRI, escitalopram. Pharmacol Biochem Behav 77:391–398PubMedCrossRefGoogle Scholar
  82. Sanchez C, Bergqvist PB, Brennum LT, Gupta S, Hogg S, Larsen A, Wiborg O (2003) 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 (Berl) 167:353–362Google Scholar
  83. Sanchez C, Bogeso KP, Ebert B, Reines EH, Braestrup C (2004) Escitalopram versus citalopram: the surprising role of the R-enantiomer. Psychopharmacology (Berl) 174:163–176CrossRefGoogle Scholar
  84. Schilstrom B, Konradsson-Geuken A, Ivanov V, Gertow J, Feltmann K, Marcus MM, Jardemark K, Svensson TH (2011) Effects of S-citalopram, citalopram, and R-citalopram on the firing patterns of dopamine neurons in the ventral tegmental area, N-methyl-D-aspartate receptor-mediated transmission in the medial prefrontal cortex and cognitive function in the rat. Synapse 65:357–367PubMedCrossRefGoogle Scholar
  85. Schulte-Herbruggen O, Fuchs E, Abumaria N, Ziegler A, Danker-Hopfe H, Hiemke C, Hellweg R (2009) Effects of escitalopram on the regulation of brain-derived neurotrophic factor and nerve growth factor protein levels in a rat model of chronic stress. J Neurosci Res 87:2551–2560PubMedCrossRefGoogle Scholar
  86. Serra-Millas M, Lopez-Vilchez I, Navarro V, Galan AM, Escolar G, Penades R, Catalan R, Fananas L, Arias B, Gasto C (2011) Changes in plasma and platelet BDNF levels induced by S-citalopram in major depression. Psychopharmacology (Berl) 216(1):1–8CrossRefGoogle Scholar
  87. 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 9:686–692PubMedCrossRefGoogle Scholar
  88. Singh SK, Yamashita A, Gouaux E (2007) Antidepressant binding site in a bacterial homologue of neurotransmitter transporters. Nature 448:952–956PubMedCrossRefGoogle Scholar
  89. Skolnick P, Popik P, Trullas R (2009) Glutamate-based antidepressants: 20 years on. Trends Pharmacol Sci 30:563–569PubMedCrossRefGoogle Scholar
  90. Steiner JA, Carneiro AM, Blakely RD (2008) Going with the flow: trafficking-dependent and -independent regulation of serotonin transport. Traffic 9:1393–1402PubMedCrossRefGoogle Scholar
  91. Storustovu S, Sanchez C, Porzgen P, Brennum LT, Larsen AK, Pulis M, Ebert B (2004) R-citalopram functionally antagonises escitalopram in vivo and in vitro: evidence for kinetic interaction at the serotonin transporter. Br J Pharmacol 142:172–180PubMedCrossRefGoogle Scholar
  92. Sutcliffe JS, Delahanty RJ, Prasad HC, McCauley JL, Han Q, Jiang L, Li C, Folstein SE, Blakely RD (2005) Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors. Am J Hum Genet 77:265–279PubMedCrossRefGoogle Scholar
  93. Tanum L, Strand LP, Refsum H (2010) Serum concentrations of citalopram—dose-dependent variation in R- and S-enantiomer ratios. Pharmacopsychiatry 43:190–193PubMedCrossRefGoogle Scholar
  94. Thompson BJ, Jessen T, Henry LK, Field JR, Gamble KL, Gresch PJ, Carneiro AM, Horton RE, Chisnell PJ, Belova Y, McMahon DG, Daws LC, Blakely RD (2011) Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter. Proc Natl Acad Sci U S A 108:3785–3790PubMedCrossRefGoogle Scholar
  95. Wade A, Friis AH (2006) The onset of effect for escitalopram and its relevance for the clinical management of depression. Curr Med Res Opin 22:2101–2110PubMedCrossRefGoogle Scholar
  96. Wade A, Gembert K, Florea I (2007) A comparative study of the efficacy of acute and continuation treatment with escitalopram versus duloxetine in patients with major depressive disorder. Curr Med Res Opin 23:1605–1614PubMedCrossRefGoogle Scholar
  97. Wade AG, Fernandez JL, Francois C, Hansen K, Danchenko N, Despiegel N (2008) Escitalopram and duloxetine in major depressive disorder: a pharmacoeconomic comparison using UK cost data. PharmacoEconomics 26:969–981PubMedCrossRefGoogle Scholar
  98. Wellsow J, Kovar KA, Machulla HJ (2002) Molecular modeling of potential new and selective PET radiotracers for the serotonin transporter. Positron emission tomography. J Pharm Pharm Sci 5:245–257PubMedGoogle Scholar
  99. Wennogle LP, Meyerson LR (1982) Serotonin modulates the dissociation of [3H]imipramine from human platelet recognition sites. Eur J Pharmacol 86:303–307PubMedCrossRefGoogle Scholar
  100. Willers ED, Newman JH, Loyd JE, Robbins IM, Wheeler LA, Prince MA, Stanton KC, Cogan JA, Runo JR, Byrne D, Humbert M, Simonneau G, Sztrymf B, Morse JA, Knowles JA, Roberts KE, McElroy JJ, Barst RJ, Phillips JA III (2006) Serotonin transporter polymorphisms in familial and idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 173:798–802PubMedCrossRefGoogle Scholar
  101. Wong EH, Nikam SS, Shahid M (2008) Multi- and single-target agents for major psychiatric diseases: therapeutic opportunities and challenges. Curr Opin Investig Drugs 9:28–36PubMedGoogle Scholar
  102. Zahniser NR, Doolen S (2001) Chronic and acute regulation of Na+/Cl−-dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems. Pharmacol Ther 92:21–55PubMedCrossRefGoogle Scholar
  103. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63:856–864PubMedCrossRefGoogle Scholar
  104. Zhang L, Rasenick MM (2010) Chronic treatment with escitalopram but not R-citalopram translocates Galpha(s) from lipid raft domains and potentiates adenylyl cyclase: a 5-hydroxytryptamine transporter-independent action of this antidepressant compound. J Pharmacol Exp Ther 332:977–984PubMedCrossRefGoogle Scholar
  105. Zhang Y, Gu F, Chen J, Dong W (2010) Chronic antidepressant administration alleviates frontal and hippocampal BDNF deficits in CUMS rat. Brain Res 1366:141–148PubMedCrossRefGoogle Scholar
  106. Zhong H, Hansen KB, Boyle NJ, Han K, Muske G, Huang X, Egebjerg J, Sanchez C (2009) An allosteric binding site at the human serotonin transporter mediates the inhibition of escitalopram by R-citalopram: kinetic binding studies with the ALI/VFL-SI/TT mutant. Neurosci Lett 462:207–212PubMedCrossRefGoogle Scholar
  107. Zhou L, Zhu DY (2009) Neuronal nitric oxide synthase: structure, subcellular localization, regulation, and clinical implications. Nitric Oxide 20:223–230PubMedCrossRefGoogle Scholar
  108. Zhou Z, Zhen J, Karpowich NK, Goetz RM, Law CJ, Reith ME, Wang DN (2007) LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake. Science 317:1390–1393PubMedCrossRefGoogle Scholar
  109. Zhou Z, Zhen J, Karpowich NK, Law CJ, Reith ME, Wang DN (2009) Antidepressant specificity of serotonin transporter suggested by three LeuT-SSRI structures. Nat Struct Mol Biol 16:652–657PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Huailing Zhong
    • 1
  • Nasser Haddjeri
    • 2
  • Connie Sánchez
    • 3
  1. 1.U-Pharm Laboratories LLCParsippanyUSA
  2. 2.Laboratory of NeuropharmacologyUniversity Claude Bernard Lyon 1LyonFrance
  3. 3.External Sourcing, Lundbeck Research USAParamusUSA

Personalised recommendations