Lexapro (Escitalopram)
Lexapro®
Classification:
Psychotropic Agents
- Antidepressants
- Selective serotonin reuptake inhibitors (SSRIs)
Description: Escitalopram (Lexapro®) is an oral selective serotonin reuptake inhibitor (SSRI). Animal studies have revealed that the biological effects on serotonin reuptake for racemic citalopram reside with the S-enantiomer (i.e., escitalopram). For humans, much of the long-term safety and efficacy data for escitalopram have been extrapolated from citalopram studies. Escitalopram is primarily used for the treatment and maintenance of major depressive disorder. Compared to placebo, escitalopram has been shown to be effective for the treatment of major depression with or without anxiety symptoms, but superiority to citalopram has not been demonstrated. In pivotal trials for depression, escitalopram demonstrated a significantly quicker onset of action (i.e., 1 to 2 weeks) than citalopram. There is no strong evidence that escitalopram is associated with a lower frequency of adverse effects than the racemic compound. Studies have shown that escitalopram is effective for anxiety disorders, including panic disorder, generalized anxiety, and social anxiety disorder. Escitalopram is approved for depression in many European countries, with additional indications for panic disorder with or without agoraphobia. The FDA approved escitalopram for use in major depressive disorder on August 15, 2002 and for depression maintenance treatment on August 29, 2002. Escitalopram was approved for generalized anxiety disorder (GAD) on December 18, 2003. Escitalopram is not FDA approved for the treatment of depression in pediatric patients.
On October 15, 2004 the FDA directed manufacturers of all antidepressants to include a Black Box warning, expanded warning statements, and clinical trial results detailing the increased risk of suicidality in children and adolescents. A Patient Medication Guide (MedGuide) will also accompany all prescriptions for antidepressants. British regulators have banned the use of some SSRIs in children in the UK. The FDA is currently assessing the risk of suicidality in adults taking antidepressants and a final report is expected by mid- to late 2006.
Mechanism of Action: Escitalopram is the the S-enantiomer of citalopram and potentiates the pharmacological effects of serotonin (5-HT) in the CNS. Like other SSRIs, escitalopram is a potent and highly selective reuptake inhibitor of serotonin. The precise mechanism of antidepressant action of SSRIs is not fully understood; however, it is believed that escitalopram and related agents inhibit reuptake of serotonin at the neuronal membrane. Escitalopram and its metabolites have low or no affinity for serotonergic(5-HT1-7), alpha- and beta- adrenergic, dopamine (D1-5), histamine (H1-3), muscarinic (M1-5), and benzodiazepine receptors.. Escitalopram also does not bind to and has low affinity for various ion channels such as Na+, K+, Cl- and Ca++ channels. The major metabolite, S(+)-desmethylcitalopram, is active in-vitro, but does not appear to contribute to human pharmacological activity. S(+)-didesmethylcitalopram is also a major metabolite of citalopram, but plasma levels are undetectable in humans. Escitalopram is at least 100 fold more potent than the R-enantiomer of citalopram with respect to inhibition of 5-HT reuptake and inhibition of 5-HT neuronal firing rate. SSRIs have less sedative, anticholinergic, and cardiovascular effects than the tricyclic antidepressant drugs due to their dramatically lower affinity for histamine, acetylcholine, and norepinephrine receptors. Monoamine oxidase is not inhibited by any SSRI. Anticholinergic activity is virtually absent.
Pharmacokinetics: Escitalopram is administered orally. Pharmacokinetic parameters are similar to citalopram. Manufacturer-sponsored pharmacokinetic studies suggest that 20 mg of escitalopram is bioequivalent to 40 mg of citalopram; however, head-to-head therapeutic interchange studies have not been performed. The absolute bioavailability of citalopram is roughly 80% and the volume of distribution is 12 L/kg; however, data are not available for escitalopram. Dosing is linear and proportional in a range of 10-30 mg/day. Absorption is not affected by food. In unpublished data, time to peak concentrations occurred roughly 5 hours following a single 20-mg dose. Peak concentrations of the major metabolite, S(+)-desmethylcitalopram occurred in 14 hours. Steady-state concentrations are achieved in roughly one week. Clinical trials suggest that a significant onset of antidepressant activity may occur by the end of the first or second week of treatment. The binding of escitalopram to plasma proteins is clinically insignificant.
Hepatic metabolism of escitalopram is the primary route for biotransformation. In-vitro studies indicated CYP3A4 and CYP2C19 are the main isozymes involved in N-demethylation of escitalopram. Escitalopram is metabolized by 3 cytochrome P450 isozymes in parallel (2C19, 2D6, and 3A4) and theoretically should have a low propensity for drug interactions. Impaired activity of any one of the isozymes due to drug interactions or genetic polymorphism is unlikely to have a large effect of net metabolic clearance. S(+)-desmethylcitalopram is the primary metabolite of escitalopram. In the plasma at steady state, the concentration of the primary metabolite is one-third that of the parent compound. S(+)-didesmethylcitalopram is a secondary metabolite; both primary and secondary metabolites have minimal biological activity in humans. In-vitro, escitalopram and its metabolites do not appear to be important inhibitors of CYP isoenzymes. Renal excretion of escitalopram is similar to citalopram with 8% excreted as the unchanged drug and 10% excreted as S(+)-desmethylcitalopram. Oral clearance is 600 ml/min, with roughly 7% due to renal clearance. Data indicate that escitalopram does enter human breast milk; placental transfer information is unavailable. The elimination half-life of escitalopram is roughly 27-32 hours and that of S(+)-desmethylcitalopram (inactive) is 59 hours.
- Special Populations: The pharmacokinetics of escitalopram may be affected by age or hepatic dysfunction, but not mild or moderate renal impairment. Pharmacokinetic parameters were compared in the younger patient versus the elderly (>= 65 years of age). Escitalopram AUC and half-life were increased by roughly 50% in the elderly, but Cmax was unchanged; the manufacturer recommends a lower escitalopram dose for the elderly. The oral clearance of citalopram has been shown to be decreased by 37% with a doubling of the half-life in patients with hepatic impairment; therefore, dose reductions are also required with escitalopram in this population. In patients with mild to moderate renal impairment, the clearance of citalopram was reduced by 17%; like with citalopram, no adjustment of escitalopram dose is needed. In patients with severe renal impairment (CrCl< 20 ml/min) there is the potential for reduced clearance as 10% of escitalopram is excreted unchanged. The manufacturer has no pharmacokinetic data or dosing recommendations for patients with severe renal impairment.
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References
. Montgomery SA, Loft H, Sanchez C, Reines EH Escitalopram (S-enantiomer of citalopram): clinical efficacy and onset of action predicted from a rat model. Pharmacol Toxicol 2001;88:282-6.
. von Moltke L, 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;29:1102-9.
. Burke WJ, Gergel I, Bose A. Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry 2002;63:331-6.
. McRae AL. Escitalopram. Curr Opin Investig Drugs 2002;3:1225-9.
. Wade A, Michael Lemming O, et al. Escitalopram 10 mg/day is effective and well-tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol 2002;17:95-102.
. Institute for Clinical Systems Improvement (ICSI). Major depression in adults for mental health care. Bloomington (MN): Institute for Clinical Systems Improvement (ICSI); 2004 May. Available on the World Wide Web at http://www.guideline.gov
. Care Management Institute, Kaiser Permanente. Adult primary care depression guidelines. Oakland (CA): Kaiser Permanente; 2004 Apr. Retrieved October 27, 2005. Available on the World Wide Web at http://www.guidelines.gov
. American Psychiatric Association practice guideline for the treatment of patients with major depressive disorder. Am J Psychiatry 2000;157(4 Suppl):1-45.
[ Revised 11/9/2005 2:10:00 PM ]
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