Escitalopram

Escitalopram

Systematic (IUPAC) name
(S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile
Identifiers
CAS number	128196-01-0
ATC code	N06AB10
PubChem	146570
DrugBank	APRD00683
ChemSpider	129277
Chemical data
Formula	C20H21FN2O
Mol. mass	324.392 g/mol (414.43 as oxalate)
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	80%
Protein binding	~56%
Metabolism	Liver, specifically the enzymes CYP3A4 and CYP2C19
Half life	27–32 hours
Excretion	?
Therapeutic considerations
Pregnancy cat.	C
Legal status	Rx Only (U.S.)
Routes	Oral
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Lexapro tablets

Cipralex brand escitalopram package and tablet sheet

Escitalopram (trade names Lexapro, Cipralex) 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 major depressive disorder and generalized anxiety disorder in adults; other indications include social anxiety disorder, panic disorder and obsessive-compulsive disorder. Escitalopram is the S-stereoisomer (enantiomer) of the earlier Lundbeck drug citalopram (Celexa), hence the name escitalopram. Escitalopram is noted for its high selectivity of serotonin reuptake inhibition and, as a result has fewer side effects not related to its serotonergic activity.^[1] According to a meta-analysis of 12 new-generation antidepressants, escitalopram and sertraline (Zoloft) are the best in terms of efficacy and acceptability in the acute-phase treatment of adults with major depression; however, sertraline may be a better choice because of the lower cost.^[2][3]

History

Escitalopram was developed in a 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.^[4] 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"^[5] - the 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 the racemic 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.^[6] 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.^[7]

In 2006 Forest Laboratories was granted an 828 day (2 years and 3 months) extension on its patent for escitalopram.^[8] This pushed the patent expiry from December 7, 2009 to March 14, 2012.

Use in depression

Despite the similarity of escitalopram and citalopram, preclinical as well as various clinical studies (including double-blinded studies) have shown differentiated effects of citalopram and escitalopram,^[9] as well as a clinical superiority compared with a variety of other SSRIs, such as paroxetine,^[10] especially in severely depressed patients. A head-to-head comparison of escitalopram with duloxetine (Cymbalta) found escitalopram to be both more tolerable and more effective.^[11]Compared with venlafaxine^[12] and sertraline^[13] escitalopram was shown to have similar efficacy.

Pharmacology

Escitalopram acts by increasing intrasynaptic levels of the neurotransmitter serotonin by blocking the reuptake of the neurotransmitter into the neuron. Of the SSRIs currently on the market escitalopram has the highest affinity for the human serotonin transporter (SERT). Another enantiomer of citalopram (R-citalopram) counteracts to a certain degree the serotonin-enhancing action of escitalopram. As a result, escitalopram is 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.^[14] Further research by the same group showed that R-citalopram also enhances binding of escitalopram,^[15] 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.^[16] 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.

Side effects and drug interactions

The side effect profile of escitalopram is close to that of other SSRIs, with nausea, somnolence (sleepiness) and gastrointestinal side effects reported as relatively common. Escitalopram, like other SSRIs,^[17] has been shown to cause sexual side effects such as decreased libido, ejaculatory delay, and anorgasmia.^[18] Escitalopram is not associated with significant weight gain. For example, 0.6 kg mean weight change after 6 months of treatment with escitalopram for depression was insignificant and similar to that with placebo (0.2 kg).^[19] 1.4-1.8 kg mean weight gain was reported in 8-month trials of escitalopram for depression,^[20] and generalized anxiety disorder.^[21] A 52-week trial of escitalopram for the long-term treatment of depression in elderly also found insignificant 0.6 kg mean weight gain.^[22] Escitalopram may help reduce weight in those treated for binge eating associated obesity.^[23]

An analysis conducted by the FDA found a statistically insignificant 1.5 to 2.4-fold (depending on the statistical technique used) increase of suicidality among the adults treated with escitalopram for psychiatric indications.^[24][25][26] Similarly, the UK MHRA data indicate an 80% increase of suicide-related events, not reaching statistical significance, in the escitalopram vs placebo patients.^[27] The authors of a related study note the general problem with statistical approaches: due to the rarity of suicidal events in clinical trials, it is hard to draw firm conclusions with a sample smaller than two million patients.^[28] A single case report described a patient developing suicidal ideation after beginning treatment with escitalopram, and suicidal ideation disappearing after stopping the treatment.^[29]

Escitalopram should be taken with caution when using St John's wort.^[30]

Discontinuation symptoms

Escitalopram discontinuation, particularly abruptly may cause certain withdrawal symptoms such as "electric shock" sensations (also known as "brain shivers" or "brain zaps"), dizziness and irritability.^[31]

Controversy

According to The New York Times, aggressive pharmaceutical marketing of escitalopram by Forest Laboratories has been controversial: the generic alternatives to the drug are cheaper, but a substantial number of doctors continue to prescribe the more expensive proprietary drug. The United States Senate Special Committee on Aging has released portions of the "Lexapro Fiscal 2004 Marketing Plan" which gives some of the details of the plans to promote use of the drug by doctors.^[32]

In 2004, two separate civil suits alleging illegal marketing of citalopram and escitalopram for use by children and teenagers by Forest were initiated by two whistleblowers. One, a non-practicing physician Joseph Piacentile makes his living filing False Claims Act suits against pharmaceutical companies. (Whistleblowers are accorded a portion of damages, if the suit wins). Another, a Forest salesman named Christopher Gobble was disturbed at what he witnessed at Forest, his first job out of school.^[33]

In February, 2009 these two suits received support from the US Attorney for Massachusetts and were combined into one. Eleven states and the District of Columbia have also filed notices of intention to intervene as plaintiffs in the action. At the time, these drugs were approved only for use by adults and the application for use of citalopram in children was specifically rejected by the FDA. Although it is not illegal for physicians to prescribe a medicine for an off-label use not approved by the Food and Drug Administration, it was illegal for Forest to actively promote the drugs for such uses. The government alleged that a research study showing lack of effectiveness when taken by children was concealed from its own medical advisers and sales personnel, as well as from researchers who conducted a study financed by the company. From 2001 to 2004, Forest heavily promoted results from another clinical trial it had financed which showed the drug was effective. Federal prosecutors also allege that the company has paid kickbacks to doctors to induce them to prescribe the medicines to children. The kickbacks allegedly included baseball tickets, a $1000 certificate to one of the most expensive New York restaurants, and paid vacations. Further, the complaint alleges that in September 2004, a Forest executive testified before Congress: “I want to emphasize that, because the FDA has not approved pediatric labeling of our products, Forest has always been scrupulous about not promoting the pediatric use of our antidepressant drugs, Celexa and Lexapro. That is the law and we follow it.”It is also alleged that the company conducted so-called "seeding studies" that were, in reality, marketing efforts to promote the drug's use by doctors.^[34][35]

Forest responded to these allegations that it "is committed to adhering to the highest ethical and legal standards, and off-label promotion and improper payments to medical providers have consistently been against Forest policy.^[36]"

References

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

External links

• Lexapro (Forest Laboratories) Official Lexapro Homepage
• Cipralex (Lundbeck) Official Cipralex Homepage
• Pharmacological information Lexapro
• portions of the "Lexapro Fiscal 2004 Marketing Plan" released by the United States Senate Special Committee on Aging