Pharmacology

Mechanism of action[edit]

Binding profile[49]
Site Ki (nM)
SERT 0.8-1.1
NET 7,800
DAT 27,400
5-HT1A >1,000
5-HT2A >1,000
5-HT2C 2,500
α1 3,900
α2 >1,000
D2 >1,000
H1 2,000
mACh 1,240

Escitalopram increases intrasynaptic levels of the neurotransmitter serotonin by blocking the reuptake of the neurotransmitter into the presynaptic neuron. Of the SSRIs currently available, escitalopram has the highest selectivity for the serotonin transporter (SERT) compared to the norepinephrine transporter (NET), making the side-effect profile relatively mild in comparison to less-selective SSRIs.[50]

Escitalopram is a substrate of P-glycoprotein and hence P-glycoprotein inhibitors such as verapamil and quinidine may improve its blood brain barrier penetrability.[51] In a preclinical study in rats combining escitalopram with a P-glycoprotein inhibitor, its antidepressant-like effects were enhanced.[51]

Interactions[edit]

Escitalopram, similarly to other SSRIs, inhibits CYP2D6 and hence may increase plasma levels of a number of CYP2D6 substrates such as aripiprazolerisperidonetramadolcodeine, etc. As escitalopram is only a weak inhibitor of CYP2D6, analgesia from tramadol may not be affected.[52] Escitalopram should be taken with caution when using St. John’s wort.[53] Exposure to escitalopram is increased moderately, by about 50%, when it is taken with omeprazole. The authors of this study suggested that this increase is unlikely to be of clinical concern.[54] Caution should be used when taking cough medicine containing dextromethorphan (DXM) as serotonin syndrome has been reported.[55]

Bupropion has been found to significantly increase citalopram plasma concentration and systemic exposure; as of April 2018 the interaction with escitalopram had not been studied, but some monographs warned of the potential interaction.[56]

Escitalopram can also prolong the QT interval and hence it is not recommended in patients that are concurrently on other medications that also have the ability to prolong the QT interval. These drugs include antiarrhythmicsantipsychoticstricyclic antidepressants, some antihistamines (astemizolemizolastine) and some antiretrovirals (ritonavirsaquinavirlopinavir).[34] Being a SSRI, escitalopram should not be given concurrently with MAOIs or other serotonergic medications.[50]

History[edit]

Cipralex brand escitalopram 10mg package and tablet sheet

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.[57]

The FDA issued the approval of escitalopram for major depression in August 2002 and for generalized anxiety disorder in December 2003. On May 23, 2006, the FDA approved a generic version of escitalopram by Teva.[58] 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.[59]

In 2006, Forest Laboratories was granted an 828-day (2 years and 3 months) extension on its US patent for escitalopram.[60] 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.

Society and culture[edit]

Allegations of illegal marketing[edit]

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 by a practicing physician named Joseph Piacentile, and the other by a Forest salesman named Christopher Gobble.[61] 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. The suits allege that Forest illegally engaged in off-label promoting of Lexapro for use in children, that the company hid the results of a study showing lack of effectiveness in children, and that the company paid kickbacks to physicians to induce them to prescribe Lexapro to children. It was also alleged that the company conducted so-called “seeding studies” that were, in reality, marketing efforts to promote the drug’s use by doctors.[62][63] 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.”[64] In 2010 Forest Pharmaceuticals Inc., agreed to pay more than $313 million to settle the charges over Lexapro and two other drugs, Levothroid and Celexa.[65]