Pharmacotherapeutic group: antidepressant, selective serotonin reuptake inhibitors. ATC-code: N06AB10.
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 1000 fold lower affinity.
Allosteric modulation of the serotonin transporter enhances binding of escitalopram to the primary binding site, resulting in more complete serotonin reuptake inhibition.
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.
Escitalopram is the S-enantiomer of the racemate (citalopram) and is the enantiomer to which the therapeutic activity is attributed. Pharmacological studies have shown that the R-enantiomer is not inert but counteracts the serotonin-enhancing and consequent pharmacological properties of the S-enantiomer.
Clinical efficacy: Major Depressive Episodes: 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-weeks) studies.
The antidepressant effect was evident as early as after two weeks for both 10 and 20 mg doses of escitalopram. After 8 weeks of therapy, escitalopram 20 mg was superior to citalopram 40 mg. A dose-response relationship for escitalopram was clearly seen in the severely depressed patients indicating that they are likely to benefit from a higher dose of escitalopram (20 mg) than the usual starting dose (10 mg).
In a long-term (24-week) double-blind study of escitalopram 10 mg vs citalopram 20 mg, escitalopram was as least as effective as citalopram, and half as many escitalopram patients withdrew because of adverse effects. 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.
Panic disorder: The efficacy of escitalopram in the treatment of panic disorder was demonstrated in a 10-week flexible dose study that compared 5-20 mg/day escitalopram to placebo and racemic citalopram 10-40 mg/day.
Escitalopram was statistically significantly superior to placebo as demonstrated by measurement of panic attack frequency, severity, duration, and accompanying symptoms. Citalopram was also efficacious compared to placebo in the majority of efficacy measures.
For the majority of treatment emergent adverse events reported for at least 5% of patients, reporting frequencies were higher in the citalopram group than in the escitalopram group.
Social Anxiety Disorder: Escitalopram was effective in both three short-term (12-week) studies and in responders in a 6 months relapse prevention study in social anxiety disorder.
In a placebo-controlled long-term study (24 weeks) efficacy of 5, 10 and 20 mg escitalopram has been demonstrated.
Escitalopram 20 mg/day was statistically significantly superior to paroxetine 20 mg/day as well as to the 5 mg/day and 10 mg/day doses of escitalopram in the treatment of social anxiety. Transient discontinuation symptoms were seen (lasting for less than 2 weeks in all active treatment groups), with significantly higher levels in paroxetine patients than in escitalopram patients (P ≤ 0.05).
In pooled data comprising 670 escitalopram-treated patients and 341 placebo-treated patients, there were 58.1% vs 40.2% responders (CGI-I score of 1 or 2) and 24.8% vs 12.9% remitters (CGI-S score of 1 or 2) (P≤0.001).
Generalised anxiety disorder: Escitalopram in doses of 10 and 20 mg/day was effective in four out of four placebo-controlled studies. 5 mg/day was not effective.
In pooled data from three studies with similar 8-week design and comprising 421 escitalopram-treated patients and 419 placebo-treated patients, there were 47.5% vs 28.9% responders and 37.1% vs 20.8% remitters (P≤0.001). Sustained effect was seen from week 1. In the fourth study (12 weeks), which included paroxetine, escitalopram 10 mg/day was significantly superior to paroxetine 20 mg/day. Transient discontinuation symptoms were seen, with significantly higher levels for paroxetine than for escitalopram 5, 10 and 20 mg/day (P≤0.01).
Escitalopram 20 mg/day significantly reduced the risk of relapse in a 24- to 76-week randomised, continuation study in 373 patients who had responded during initial 12-week open label treatment.
Obsessive-compulsive disorder: In the short-term (12 weeks), 20 mg/day escitalopram separated from placebo on the Y-BOCS total score and the Y-BOCS subscales scores of obsessions and rituals, and also on the NIMH-OCS total score. In the observed cases analysis, both 10 mg/day (p=0.005) and 20 mg/day (p<0.001) escitalopram were effective.
The long-term maintenance effect has been demonstrated in two studies; a 24 weeks placebo-controlled, dose-finding study and a 16 weeks placebo-controlled, relapse-prevention study.
In the long-term, 24-week, placebo-controlled, dose-finding study, both 10 mg/day (p<0.05) and 20 mg/day (p<0.01) escitalopram were significantly more effective than placebo, as measured by the primary outcome measure, the Y-BOCS total, as well as on the secondary subscales of the Y-BOCS obsessions and rituals, and the NIMH-OCS (10 mg/day (p<0.01) and 20 mg/day (p<0.001) escitalopram).
Maintenance of efficacy and prevention of relapse was demonstrated for 10 and 20 mg/day escitalopram in patients who responded to escitalopram in a 16-week open treatment phase and who were entering a 24-week (double blind placebo controlled randomized) relapse prevention trial. In the observed relapse prevention trial, both 10 mg/day (p=0.014) and 20 mg/day (p<0.001) escitalopram showed significantly fewer relapses.
A significant and beneficial effect of escitalopram on quality of life was observed (as assessed by the SF-36 and SDS) in the OCD studies with escitalopram.
Pharmacokinetics: Absorption: Absorption is almost complete and independent of food intake. Mean time to maximum concentration (mean Tmax) is 4 hours after multiple dosing. As with racemic citalopram, the absolute bio-availability of escitalopram is expected to be about 80%.
Distribution: The apparent volume of distribution (Vd,β/F) after oral administration is about 12 to 26 L/kg. The plasma protein binding is below 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 (t½ β) after multiple dosing is about 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.
Linearity: There is linear pharmacokinetics. Steady-state plasma levels are achieved in about 1 week. Average steady-state concentrations of 50 nmol/L (range 20 to 125 nmol/L) are achieved at a daily dose of 10 mg.
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 (see Dosage & Administration).
Reduced hepatic function: In patients with mild or moderate hepatic impairment (Child-Pugh Criteria A and B), the half-life of escitalopram was about twice as long and the exposure was about 60% higher than in subjects with normal liver function (see Dosage & Administration).
Reduced renal function: With racemic citalopram, a longer half-life and a minor increase in exposure have been observed in patients with reduced kidney function (CLcr 10-53 ml/min). Plasma concentrations of the metabolites have not been studied, but they may be elevated (see Dosage & Administration).
Polymorphism: It has been observed that poor metabolisers with respect to CYP2C19 have twice as high a plasma concentration of escitalopram as extensive metabolisers. No significant change in exposure was observed in poor metabolisers with respect to CYP2D6 (see Dosage & Administration).
Toxicology: Preclinical safety data: No complete conventional battery of preclinical studies was performed with escitalopram since the bridging toxicokinetic and toxicological studies conducted in rats with escitalopram and citalopram showed a similar profile. Therefore, all the citalopram information can be extrapolated to escitalopram.
In comparative toxicological studies in rats, escitalopram and citalopram caused cardiac toxicity, including congestive heart failure, after treatment for some weeks, when using dosages that caused general toxicity. The cardiotoxicity seemed to correlate with peak plasma concentrations rather than to systemic exposures (AUC). Peak plasma concentrations at no-effect-level were in excess (8-fold) of those achieved in clinical use, while AUC for escitalopram was only 3- to 4-fold higher than the exposure achieved in clinical use. For citalopram, AUC values for the S-enantiomer were 6- to 7-fold higher than exposure achieved in clinical use. These findings are probably related to an exaggerated influence on biogenic amines i.e. secondary to the primary pharmacological effects, resulting in haemodynamic effects (reduction in coronary flow) and ischaemia. However, the exact mechanism of cardiotoxicity in rats is not clear. Clinical experience with citalopram and the clinical trial experience with escitalopram do not indicate that these findings have clinical correlate.
Increased content of phospholipids has been observed in some tissues e.g. lung, epididymides and liver after treatment for longer periods with escitalopram and citalopram in rats. Findings in the epididymides and liver were seen at exposures similar to that in man. The effect is reversible after treatment cessation. Accumulation of phospholipids (phospholipidosis) in animals has been observed in connection with many cationic amphiphilic medicines. It is not known if this phenomenon has any significant relevance for man.
In the developmental toxicity study in the rat, embryotoxic effects (reduced foetal weight and reversible delay of ossification) were observed at exposures in terms of AUC in excess of the exposure achieved during clinical use. No increased frequency of malformations was noted. A pre- and postnatal study showed reduced survival during the lactation period at exposures in terms of AUC in excess of the exposure achieved during clinical use.
Animal data have shown that some SSRIs induces a reduction of fertility index and pregnancy index, reduction in number in implantation and abnormal sperm at exposure well in excess of human exposure. No animal data related to this aspect are available for escitalopram.