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128196-01-0 ESCITALOPRAM

Escitalopram (also known under various trade names) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults and children over 12 years of age with major depressive disorder and generalized anxiety disorder. Escitalopram is the (S)-stereoisomer (enantiomer) of the earlier Lundbeck drug citalopram, hence the name escitalopram. Escitalopram is noted for its high selectivity with serotonin reuptake inhibition. The similarity between escitalopram and citalopram has led to accusations of “evergreening“, an accusation that Lundbeck has rejected.^[1]

Escitalopram has FDA approval for the treatment of major depressive disorder and generalized anxiety disorder in adults.^[2]

Off-label uses

Escitalopram is sometimes prescribed off-label for the treatment of other conditions: social anxiety disorder,^[3] panic disorder^[4]and obsessive-compulsive disorder.^[5] There is some evidence favouring escitalopram over the antidepressants citalopram andfluoxetine in the first two weeks of major depression.^[6] Concerns of sponsorship bias with the studies are however noted.^[6] In another review escitalopram and sertraline had the highest rate of efficacy and acceptability among adults receiving treatment for major depression with second-generation antidepressants.^[7]

Efficacy

There is some controversy over selective publishing of SSRI clinical trials.^[8] A meta-analysis analyzing published as well as unpublished trials found placebos to be similarly effective to SSRIs in treating mild depression, although SSRIs were more effective than placebo in more severe cases, with the magnitude of SSRI superiority increasing with increasing depression severity.^[9]

A series of randomized, double-blind trials have found Escitalopram to be more efficacious and have fewer adverse effects than Citalopram.^{[10][11][12][13]} Meta-analysis show a “small” but statistically significant improvement in effect strength ^[14][15] and some dispute these findings.^[16]

Pharmacology

Cipralex brand escitalopram 10mg package and tablet sheet

Escitalopram increases intrasynaptic levels of the neurotransmitter serotonin by blocking the reuptake of the neurotransmitter into the presynaptic neuron. Of the SSRIs currently on the market, escitalopram has the highest affinity for the human serotonin transporter (SERT). The enantiomer of escitalopram ((R)-citalopram) counteracts to a certain degree the serotonin-enhancing action of escitalopram. As a result, escitalopram has been claimed to be a more potent antidepressant than citalopram, which is a mixture of escitalopram and (R)-citalopram. In order to explain this phenomenon, researchers from Lundbeck proposed that escitalopram enhances its own binding via an additional interaction with another allosteric site on the transporter.^[42] Further research by the same group showed that (R)-citalopram also enhances binding of escitalopram,^[43] and therefore the allosteric interaction cannot explain the observed counteracting effect. In the most recent paper, however, the same authors again reversed their findings and reported that R-citalopram decreases binding of escitalopram to the transporter.^[44] Although allosteric binding of escitalopram to the serotonin transporter is of unquestionable research interest, its clinical relevance is unclear since the binding of escitalopram to the allosteric site is at least 1000 times weaker than to the primary binding site.

In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of escitalopram. The resulting metabolites, desmethylescitalopram and didesmethylescitalopram, are significantly less active and their contribution to the overall action of escitalopram is negligible.

History

Escitalopram was developed in close cooperation between Lundbeck and Forest Laboratories. Its development was initiated in the summer of 1997, and the resulting new drug application was submitted to the U.S. FDA in March 2001. The short time (3.5 years) it took to develop escitalopram can be attributed to the previous extensive experience of Lundbeck and Forest with citalopram, which has similar pharmacology.^[45] The FDA issued the approval of escitalopram for major depression in August 2002 and for generalized anxiety disorder in December 2003. Escitalopram can be considered an example of “evergreening“^[46] (also called “lifecycle management”^[47])– the long-term strategy pharmaceutical companies use in order to extend the lifetime of a drug, in this case of the citalopram franchise. Escitalopram is an enantiopure compound of theracemic mixture citalopram, used for the same indication, and for that reason it required less investment and less time to develop. Two years after escitalopram’s launch, when the patent on citalopram expired, the escitalopram sales successfully made up for the loss. On May 23, 2006, the FDA approved a generic version of escitalopram by Teva.^[48]On July 14 of that year, however, the U.S. District Court of Delaware decided in favor of Lundbeck regarding the patent infringement dispute and ruled the patent on escitalopram valid.^[49]

In 2006 Forest Laboratories was granted an 828 day (2 years and 3 months) extension on its US patent for escitalopram.^[50] This pushed the patent expiration date from December 7, 2009 to September 14, 2011. Together with the 6-month pediatric exclusivity, the final expiration date was March 14, 2012.

Brand names

Escitalopram is sold under the following brand names:

References

• “A Drug Maker’s Playbook Reveals a Marketing Strategy” article in The New York Times by Gardiner Harris, September 1, 2009

• Royal Pharmaceutical Society of Great Britain (September 2009). British National Formulary (BNF 58). UK: BMJ Group and RPS Publishing. ISBN 978-0-85369-778-7.

• U.S. National Library of Medicine: Drug Information Portal — Escitalopram
• Lexapro (Forest Laboratories) Official Lexapro homepage
• Cipralex (Lundbeck) Official Cipralex homepage
• Pharmacological information Lexapro
• Cipla Medpro Official Cipla Medpro homepage

http://www.sciencedirect.com/science/article/pii/S0040402011015249

http://www.sciencedirect.com/science/article/pii/S0040402011015249