Escitalopram Sandoz Mechanism of Action

Pharmacotherapeutic Group: Antidepressants, selective serotonin reuptake inhibitors. ATC Code: N06AB10.
Pharmacology: Pharmacodynamics: Mechanism of Action: Escitalopram is a selective inhibitor of serotonin reuptake with little to no effect on norepinephrine or dopamine reuptake.
Escitalopram has no or very low affinity for 5-HT1-7m alpha-and beta-adrenergic, D1-5, H1-3, M1-5, and benzodiazepine receptors. The inhibition of 5-HT reuptake is the only likely mechanism of action explaining the pharmacological and clinical effects of escitalopram.
Pharmacodynamics Effects: In a double-blind, placebo-controlled ECG study in healthy subjects, the change from baseline in QTc (Fridericia-correction) was 4.3 msec (90% CI: 2.2, 6.4) at the 10 mg/day dose and 10.7 msec (90% CI: 8.6, 12.8) at the supratherapeutic dose of 30 mg/day (see Contraindications, Precautions, Interactions, Adverse Reactions and Overdosage).
Clinical Efficacy: Major depressive episodes: In a longer-term study, 274 adults with major depressive disorder who had responded to escitalopram 10 or 20 mg daily during an initial 8-week, open-label, flexible dosage treatment phase were randomized to continue escitalopram at the same dosage or receive placebo for up to 36 weeks of observation for relapse in the double-blind phase. Relapse during the double-blind phase was defined as an increase in the MADRS total score to 22 or greater or discontinuance due to insufficient clinical response. Escitalopram-treated patients experienced a substantially longer time to relapse of depression compared with those receiving placebo.
Social anxiety disorder: Escitalopram was effective in both three short-term (12- week) studies and in responders in a 6-month relapse prevention study in social anxiety disorder. In a 24-week dose-finding study, efficacy of 5, 10 and 20 mg escitalopram has been demonstrated.
Generalised 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 week, randomised, maintenance of efficacy study in 373 patients who had responded during the initial 12-week open-label treatment.
Obsessive-compulsive disorder: In a randomised, double-blind, clinical study, 20 mg/day escitalopram separated from placebo on the Y-BOCS total score after 12 weeks. After 24 weeks, both 10 and 20 mg/day escitalopram were superior as compared to placebo.
Prevention of relapse was demonstrated for 10 and 20 mg/day escitalopram in patients who responded to escitalopram in a 16-week open-label period and who entered a 24-week, randomised, double-blind, placebo controlled period.
Pharmacokinetics: Absorption: Time to peak: Escitalopram : ~ 5 hours
Distribution: The volume of distribution (V_d,) is about 20l/kg. Protein binding: ~ 56% to plasma proteins.
Biotransformation: Metabolism: Hepatic via CYP2C19 and 3A4 to S-desmethylcitalopram (S-DCT); S-DCT is metabolized to S-didesmethylcitalopram (S-DDCT) via CYP2D6; in vitro data suggest metabolites do not contribute significantly to the antidepressant effects of escitalopram.
Elimination: Half-life elimination: ~ 27-32 hours (increased ~50% in the elderly and doubled in patients with hepatic impairement).
Excretion: Urine(8% as unchanged drug; S-DCT 10%).
Elderly patients (> 65 years of age): 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 halflife of escitalopram was about twice as long and higher than in subjects with normal liver function (see Dosage & Administration).
Reduced renal function: Escitalopram should be used with caution in patient with severe renal impairment (ie., creatinine clearance less than 20 ml/minute).
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. The 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 a 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 citalopram 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.