Pharmacology: Pharmacodynamics: Mechanism of action: Escitalopram is a selective inhibitor of serotonin (5-HT) re-uptake with high affinity for the primary binding site. It also binds to an allosteric site on the serotonin transporter, with a 100 fold lower affinity.
Escitalopram has no or low affinity for a number of receptors including 5-HT1A, 5-HT2, DA, D1 and D2 receptors, α1-, α2-, β-adrenoceptors, histamine H1, muscarine cholinergic, benzodiazepine, and opioid receptors.
The inhibition of 5-HT re-uptake is the only likely mechanism of action explaining the pharmacological and clinical effects of escitalopram.
Clinical efficacy: Major depressive episodes: It is reported that escitalopram has been found to be effective in the acute treatment of major depressive episodes in three out of four double-blind, placebo controlled short-term (8-week) studies. In a long-term relapse prevention study, 274 patients who had responded during an initial 8-week open label treatment phase with escitalopram 10 or 20 mg/day, were randomised to continuation with escitalopram at the same dose, or to placebo, for up to 36 weeks. In this study, patients receiving continued escitalopram experienced a significantly longer time to relapse over the subsequent 36 weeks compared to those receiving placebo.
Generalized anxiety disorder: Escitalopram in doses of 10 and 20 mg/day was effective in four out of four placebo controlled studies.
In pooled data from three studies with similar design comprising 421 escitalopram treated patients and 419 placebo-treated patients, there were 47.5% and 28.9% responders, respectively and 37.1% and 20.8% remitters. Sustained effect was seen from week 1.
Maintenance of efficacy of escitalopram 20mg/day was demonstrated in a 24 to 76 weeks, randomized, maintenance of efficacy study in 373 patients who had responded during the initial 12-week open-label treatment.
Pharmacokinetics: Absorption: Absorption is almost complete and independent of food intake. (Mean time to maximum concentration (mean Tmax) is 4 hours after multiple dosing).
Tablets: As with racemic citalopram, the absolute bioavailability of escitalopram is expected to be about 80%.
Distribution: The apparent volume of distribution after oral administration is about 12 to 26 L/kg. The plasma protein binding is about 80% for escitalopram and its main metabolites.
Biotransformation: Escitalopram is metabolised in the liver to the demethylated and didemethylated metabolites. Both of these are pharmacologically active. Alternatively, the nitrogen may be oxidised to form the N-oxide metabolite. Both parent substance and metabolites are partly excreted as glucuronides. After multiple dosing, the mean concentrations of the demethyl and didemethyl metabolites are usually 28-31% and <5%, respectively, of the escitalopram concentration. Biotransformation of escitalopram to the demethylated metabolite is mediated primarily by CYP2C19. Some contribution by the enzymes CYP3A4 and CYP2D6 is possible.
Elimination: The elimination half-life of escitalopram is 30 hours and the oral plasma clearance (Cloral) is about 0.6 L/min. The major metabolites have a significantly longer half-life. Escitalopram and major metabolites are assumed to be eliminated by both the hepatic (metabolic) and the renal routes, with the major part of the dose excreted as metabolites in the urine.
There is linear pharmacokinetics. Steady-state plasma levels are achieved in about 7 days.
Elderly patients (>65 years): Escitalopram appears to be eliminated more slowly in elderly patients compared to younger patients. Systemic exposure (AUC) is about 50% higher in elderly compared to young healthy volunteers, and by 30% in a multiple-dose study.
It has been suggested that these differences in pharmacokinetic parameters may reflect declining liver and kidney function.