- 220 Downloads
Escitalopram is the therapeutically active S-enantiomer of RS-citalopram, a commonly prescribed SSRI. The R-enantiomer is essentially pharmacologically inactive.
Escitalopram 10 or 20 mg/day produced significantly greater improvements in standard measurements of antidepressant effect (Montgomery-Åsberg Depression Rating Scale [MADRS], Clinical Global Impressions Improvement and Severity scales [CGI-I and CGI-S] and Hamilton Rating Scale for Depression [HAM-D]) in patients with major depressive disorder (MDD) than placebo in several 8-week, placebo-controlled, randomised, double-blind, multicentre studies. Symptom improvement was rapid, with some parameters improving within 1–2 weeks of starting escitalopram treatment. In addition, escitalopram showed earlier and clearer separation from placebo than RS-citalopram, at one-quarter to half the dosage, in 8-week, placebo-controlled trials; had significantly better efficacy than RS-citalopram in a subgroup of patients with moderate MDD in a 24-week trial; and produced sustained response and remission significantly faster than venlafaxine extended release in patients with MDD. Escitalopram reduced relapse rate compared with placebo and increased the percentage of patients in remission in long-term trials (up to 52 weeks).
Consistently significant improvements for all efficacy parameters were also observed in patients with generalised anxiety disorder, social anxiety disorder and panic disorder treated with escitalopram for 8–12 weeks in individual, randomised, placebo-controlled, double-blind investigations.
The good tolerability profile of escitalopram is predictable and similar to that of RS-citalopram. Such adverse events as nausea, ejaculatory problems, diarrhoea and insomnia are expected but, with the exception of ejaculatory problems and nausea, which is mild and transient, these were generally no more frequent than with placebo in fully published clinical trials. No adverse events not previously seen in acute trials were reported with long-term use.
Conclusions: Escitalopram, the S-enantiomer of RS-citalopram, is a highly selectiveinhibitor for the serotonin transporter, ameliorates depressive symptoms in patients with MDD at half the RS-citalopram dosage, has a rapid onset of symptom improvement and has a predictable tolerability profile of generally mild adverse events. Like RS-citalopram, escitalopram is expected to have a low propensity for drug interactions, a potential benefit in the management of patients with comorbidities. In combination, these properties place escitalopram, like other SSRIs, as first-line therapy in patients with MDD. Escitalopram is indicated for use in patients with panic disorder in Europe and, should further evidence confirm early findings that escitalopram reduces anxiety, the drug may well find an additional role in the management of anxiety disorders.
Escitalopram is the therapeutically active S-enantiomer of RS-citalopram, which is a highly selective and effective serotonin reuptake inhibitor. The antidepressant mechanism of escitalopram is presumed to be a result of stimulation of serotonergic neurotransmission in the CNS as a consequence of higher serotonin levels resulting from inhibition of the serotonin transporter.
Escitalopram has no or very low affinity for a variety of other serotonin, dopamine, α- and β-adrenergic, histamine, muscarinic and benzodiazepine receptors. It also does not bind to or has low affinity for a range of ion channels including those for Na+], K+], Cl-] and Ca2+].
In rat models predictive of antidepressant activity, escitalopram demonstrated higher activity than RS- citalopram. The minimum effective dose was 4-fold lower with escitalopram than with RS-citalopram in reducing aggressive behaviour in the resident-intruder rat model and in reducing panic-like anxiety in rats after electrical stimulation of the dorsal peri-aquaductal grey matter. A trial using a conditioned fear model in rats found that escitalopram reversed suppression of exploratory activity more rapidly than a comparable dose of S-citalopram in RS-citalopram. This qualitative difference between S-citalopram and RS-citalopram was confirmed by another in vivo trial that showed higher extracellular serotonin concentrations in the frontal cortex of rats after injection with escitalopram than in rats treated with a racemic mixture of S-citalopram and R-citalopram, indicating inhibition of the S-enantiomer by the R-enantiomer in the racemate.
Escitalopram shows linear and dose-proportional pharmacokinetics with steady—state plasma concentrations achieved in 1 week in healthy volunteers. The mean steady-state area under the plasma concentration-time curve (0–24h) after a dosage of 10 mg/day was 360.2 ng · h/mL in healthy volunteers.
After a single dose of escitalopram 20mg, peak plasma concentrations were reached in 4–5 hours and were not affected by food intake. Absolute bioavailability of RS-citalopram is about 80% and binding to human plasma proteins of escitalopram is approximately 56%. The apparent volume of distribution of escitalopram after oral administration is 12–26 L/kg. The pharmacokinetic profile of the S-enantiomer is the same whether given as escitalopram 10mg or RS-citalopram 20mg.
Escitalopram is transformed to two metabolites, S-demethylcitalopram and S-didemethylcitalopram, both of which are much less potent than the parent drug. Alernatively, the nitrogen atom may be oxidised to the N-oxide metabolite. Escitalopram is the predominant plasma compound. The primary isoenzymes involved in metabolising escitalopram are cytochrome P450 (CYP) 2C19, CYP3A4 and CYP2D6.
Elimination of escitalopram is principally via hepatic and renal routes as metabolites. Oral clearance of escitalopram is 36 L/h (600 mL/min) and the elimination half-life (t1/2) is between 27 and 32 hours.
There are no sex-related differences in escitalopram pharmacokinetics; however, escitalopram is eliminated more slowly in the elderly but maximum plasma concentration is unchanged thus increasing systemic exposure. In addition, oral clearance of RS-citalopram was reduced by 37% and t1/2; doubled in patients with hepatic impairment.
Antidepressive efficacy was observed in patients with major depressive disorder (MDD) in 8-week trials with significant improvements in Montgomery-Åsberg Depression Rating Scale (MADRS) scores in patients receiving escitalopram 10 or 20 mg/day versus those receiving placebo noted as early as 1–2 weeks after starting therapy. Follow-on studies found that escitalopram reduced the long-term risk of relapse and continued to reduce MADRS scores. Significant improvements ere also observed in all secondary efficacy parameters including the Hamilton Rating Scale for Depression (HAM-D) and the Clinical Global Impressions Improvement and Severity scales (CGI-I and CGI-S) scores, and at least half of patients receiving escitalopram responded to treatment.
Escitalopram showed earlier and better efficacy than RS-citalopram in a subgroup of patients with moderate MDD after 24 weeks and produced sustained response and remission significantly more rapidly (p < 0.05) than venlafaxine extended release (XR) at several timepoints over 8 weeks in patients with this disorder. In addition, improvements in quality of life (QOL) were experienced in the one study to report this.
Significantly greater reductions in Hamilton Rating Scale for Anxiety (HAM-A) scores were observed in 124 patients, meeting the DSM-IV criteria for generalised anxiety disorder (GAD), who received escitalopram than in 128 patients meeting the same criteria who received placebo for 8 weeks. Improvements were also observed in several secondary efficacy parameters in the patients receiving escitalopram.
In a 12-week study in patients who met the DSM-IV criteria for social anxiety disorder (SAD), those receiving escitalopram (n = 181 ) showed greater reductions in all SAD measurement scores and in disability scores than those receiving placebo (n = 177). The primary efficacy parameter was changes in Liebowitz Social Anxiety Scale scores from baseline to week 12. Secondary efficacy parameters included CGI-I scores, changes in CGI-S scores and Sheehan Disability scores over the same period.
Escitalopram was significantly more effective than placebo in the treatment of panic disorder for all efficacy parameters in a 10-week trial. Efficacy measurements included frequency of panic attacks, the Panic and Anticipatory Anxiety Scale, Panic and Agoraphobia Scale, HAM-A, CGI-I and CGI-S scores, the Patient Global Evaluation and a QOL questionnaire. Improvements were apparent by week 4 in patients with GAD or panic disorder.
Two decision analytic studies carried out in Finland and Sweden found that, when used to treat MDD, escitalopram was more cost effective than RS-citalopram, fluoxetine or venlafaxine. In addition, the Finnish study found that cost utility (cost per quality-adjusted life-year gained) was greater for escitalopram than for the other three drugs.
The adverse events profile for escitalopram is similar to that observed with RS-citalopram in both MDD and anxiety disorders. Discontinuation rates due to adverse events were similar in patients receiving escitalopram or placebo in several trials.
Nausea and ejaculatory problems were reported in both fully published trials in patients with MDD. In addition, diarrhoea, insomnia, dry mouth, headache and upper respiratory tract infections were experienced by patients receiving escitalopram, although the incidence of these events was not significantly higher than in patients receiving placebo.
Fewer patients receiving escitalopram withdrew because of adverse events than patients treated with venlafaxine XR.
A 52-week follow-on trial found no difference in the adverse events profile for escitalopram than that observed in 8-week, double-blind studies.
The adverse events profile from three trials in patients with GAD, SAD or panic disorder receiving escitalopram was similar to that observed in patients with MDD. The withdrawal rate because of adverse events was low and similar to that of placebo.
Dosage and Administration
The recommended dosage of escitalopram tor the treatment of MDD is 10 mg/day which, depending on the individual patient response, may be titrated to a maximum dosage of 20 mg/day. In Europe, escitalopram is also approved for the treatment of panic disorder; the recommended initial dosage is 5 mg/day for 1 week then titrated to 10 mg/day. The dosage may be further increased to 20 mg/ day, dependent on patient response to treatment. Administration is once daily in the morning or evening and escitalopram may be taken with or without food.
In elderly patients or patients with hepatic impairment, the maximum recommended dosage is 10 mg/day. In Europe, it is recommended that treatment be initiated at 5 mg/day in these patients. No dosage adjustment is required in patients with mild to moderate renal impairment; however, escitalopram should be used with caution in patients with severe renal impairment.
Escitalopram is contraindicated in combination with irreversible monoamine oxidase inhibitors (MAOIs) and a period of at least 2 weeks should be allowed between discontinuation of escitalopram and commencement of an irreversible MAOI and vice versa.
- 1.Montgomery SA. New developments in the treatment of depression. J Clin Psychiatry 1999; 60 Suppl. 14: 10–5Google Scholar
- 5.Keller MB. The long-term treatment of depression. J Clin Psychiatry 1999; 60 Suppl. 17: 41–5Google Scholar
- 6.Thase ME. Long-term nature of depression. J Clin Psychiatry 1999; 60 Suppl. 14: 3–9Google Scholar
- 7.Ballenger JC, Davidson JRT, Lecrubier Y, et al. Consensus statement on the primary care management of depression from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry 1999; 60 Suppl. 7: 54–61Google Scholar
- 20.Forest Pharmaceuticals Inc. Escitalopram (Lexapro) prescribing information [online]. Available from URL: http://www.lexapro.com [Accessed 2002 Aug 21]
- 21.Lundbeck. Escitalopram prescribing information [online]. Available from URL: http://www.cipralex.com/1.4_prescribing_information.asp [Accessed 2002 Aug 22]
- 22.Sánchez C, Larsen AK, Brennum LT, et al. Escitalopram, an extremely selective serotonin reuptake inhibitor [abstract no. P.1.E.053]. Int J Neuropsychopharmacol 2002 Jun; 5Suppl. 1: S66 plus poster presented at the 23rd CINP Congress, 2002 Jun 23-27, MontrealGoogle Scholar
- 24.Sánchez C, Hogg S. The antidepressant activity of RS-citalopram resides in the S-enantiomer (Lu 26-054) [abstract no. 292]. Biol Psychiatry 2000 Apr 15; 47 Suppl.: 88S–9SGoogle Scholar
- 25.Sánchez C, Brennum LT. The S-enantiomer of RS-citalopram (Lu 26-054) is a highly selective and potent serotonin reuptake inhibitor [abstract no. 291]. Biol Psychiatry 2000 Apr 15; 47 Suppl.: 88SGoogle Scholar
- 27.Mitchell PJ, Hogg S. Behavioral effects of escitalopram predict potent antidepressant activity [abstract no. 401]. Biol Psychiatry 2001 Apr 15; 49 Suppl.: 115SGoogle Scholar
- 28.Mork A, Kreilgaard M, Sanchez C, et al. In vitro and in vivo effects of citalopram and its enantiomers on the serotonin uptake transporter [abstract no. P.1.135]. J Eur Neuropsychopharmacol 2002 Oct; 12Suppl. 3: S224 plus poster presented at the 15th ECNP Congress, 2002 Oct 5-9, BarcelonaCrossRefGoogle Scholar
- 29.Hogg S, Jessa M. The effects of escitalopram in the dorsal periaquaductal grey stimulation model of panic anxiety [abstract]. Int J Neuropsychopharmacol 2002 Jun; 5Suppl. 1: 151–2 plus poster presented at the 23rd CINP Congress, 2002 Jun 23–27, MontrealGoogle Scholar
- 30.Papp M, Sanchez C. Escitalopram potently reverses conditioned footshock-induced suppression of exploratory activity in rats: an animal model of generalised anxiety [abstract no. P.3.043 plus poster]. 15th ECNP Congress; 2002 Oct 5–9; BarcelonaGoogle Scholar
- 31.Gutierrez M, Mengel H. Pharmacokinetics of escitalopram [poster]. 42nd Annual New Clinical Drug Evaluation Unit Meeting; 2002 Jun 10–13; Boca RatonGoogle Scholar
- 34.Greenblatt DJ, von Moltke LL, Giancarlo OGM, et al. Escitalopram metabolism in vitro [abstract]. Clin Pharmacol Ther 2001 Feb; 69(2): P49Google Scholar
- 35.von Moltke LL, Greenblatt DJ, Giancarlo GM, et al. Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram. Drug Metab Dispos 2001 Aug; 29(8): 1102–9Google Scholar
- 38.Gutierrez M, Abramowitz W. Lack of a pharmacokinetic interaction between escitalopram and the CYP3A4 inhibitor ritonavir [abstract no. 181]. Biol Psychiatry 2001 Apr; 49 Suppl.: 51SGoogle Scholar
- 41.Montgomery SA, Loft H, Reines EH. Escitalopram 10mg/day: effective antidepressants in primary care patients [abstract]. American Psychiatric Association Annual Meeting; 2001 May 5; New Orleans, 179Google Scholar
- 42.Lepola U, Loft H, Reines EH. Escitalopram is efficacious and well tolerated for the treatment of depression in primary care [abstract]. Eur Neuropsychopharmacol 2001 Oct; 11 Suppl. 3: 232Google Scholar
- 44.Wade A, Despiegel N, Reines E. Depression in primary care patients: improvement during long-term escitalopram treatment [abstract no. P.1.156]. J Eur Neuropsychopharmacol 2002 Oct; 12Suppl. 3: S224 plus poster presented at the 15th ECNP Congress, 2002 Oct 5–9, BarcelonaGoogle Scholar
- 45.Montgomery SA, Huusom AKT, Bothmer J. Escitalopram is a new and highly efficaceous SSRI in the treatment of major depressive disorder [abstract no. P.1.206]. J Eur Neuropsychopharmacol 2002 Oct; 12Suppl. 3: S224 plus poster presented at the 15th ECNP Congress, 2002 Oct 5–9, BarcelonaGoogle Scholar
- 46.Colonna L, Reines EH, Andersen HF. Escitalopram is well tolerated and more efficacious than citalopram in long-term treatment of moderately depressed patients. Int J Psych Clin Prac 2002; 6: 243–4 plus poster presented at the 3rd International Forum on Mood and Anxiety Disorders, 2002 Nov 27–30, Monte CarloGoogle Scholar
- 47.Davidson J, Bose A, Su G. Escitalopram in the treatment of generalized anxiety disorder [abstract]. Int J Neuropsychopharmacol 2002 Jun; 5Suppl. 1: 214 plus poster presented at the 12th World Congress of Psychiatry, 2002 Aug 24-29, YokohamaGoogle Scholar
- 48.Kasper S, Loft H, Smith JR. Escitalopram is efficacious and well tolerated in the treatment of SAD [abstract]. Int J Neuropsychopharmacol 2002; 5Suppl. 1: S131 plus poster presented at the 23rd CINP Congress, 2002 Jun 23–27, MontrealGoogle Scholar
- 49.Stahl S, Gergel I, Li D. Escitalopram in the treatment of panic disorder. Int J Neuropsychopharmacol 2002; 5Suppl. 1: S217 plus poster presented at the 23rd CINP Congress, 2002 Jun 23-27, MontrealGoogle Scholar
- 51.Lundbeck H. Efficacy results for escitalopram. 2003. (Data on file)Google Scholar
- 52.François C, Sintonen H, Toumi M. Introduction of escitalopram, a new SSRI in Finland: comparison of cost effectiveness between the other SSRIs and SNRI for the treatment of depression and estimation of the budgetry impact. J Drug Assess 2002; 5: 221–37Google Scholar
- 54.Montgomery SA. Escitalopram offers early separation from placebo in the treatment of depression [abstract]. J Eur Neuropsychopharmacol 2002 Oct; 12Suppl. 3: S231Google Scholar
- 55.Wade A. Long-trem treatment of depression with escitalopram is safe and well tolerated. Int J Neuropsychopharmacol 2002; 5Suppl. 1: S146Google Scholar
- 62.Lydiard RB. Effects of escitalopram on anxiety symptoms in depression [abstract]. American Psychiatric Association Annual Meeting; 2001 May 5–10; New Orleans, 276Google Scholar
- 64.Nutt DJ. Care of depressed patients with anxiety symptoms. J Clin Psychiatry 1999; 60 Suppl. 17: 23–7Google Scholar