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 CID 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
Therapeutic considerations
Pregnancy cat. C
Legal status Rx Only (U.S) POM (U.K)
Routes Oral
 YesY(what is this?)  (verify)
Lexapro tablets
Cipralex brand escitalopram package and tablet sheet

Escitalopram (trade names Lexapro, Cipralex, Seroplex) 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 in adults with major depressive disorder, generalized anxiety disorder, social anxiety disorder , or panic disorder. Escitalopram is the S-stereoisomer (enantiomer) of the earlier Lundbeck drug citalopram, hence the name escitalopram. Escitalopram is noted for its high selectivity of serotonin reuptake inhibition and has side effects typical for the SSRI class.

Contents

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.[1] 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"[2] (also called "lifecycle management"[3])– 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 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.[4] 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.[5]

In 2006 Forest Laboratories was granted an 828 day (2 years and 3 months) extension on its US patent for escitalopram.[6] 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,[7] as well as a clinical superiority compared with a variety of other SSRIs, such as paroxetine,[8] especially in severely depressed patients. A head-to-head comparison of escitalopram with duloxetine found escitalopram to be both more tolerable and more effective.[9] Compared with venlafaxine[10] and sertraline[11], escitalopram was shown to have similar efficacy.

According to a meta-analysis of 12 new-generation antidepressants, escitalopram and sertraline 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.[12][13]

Dosage usually ranges from 10 mg/day ranging to a maximum recommended dose of 20 mg/day. For elderly people or people with GI problems, the maximum recommended dose is 10 mg/day.[14]

Pharmacology

Escitalopram increases 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.[15] Further research by the same group showed that R-citalopram also enhances binding of escitalopram,[16] 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.[17] 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.

Side effects and drug interactions

The side effect profile of escitalopram is similar to that of other SSRIs. For example, according to the FDA analysis of depression trials common side effects for the highest approved dose of escitalopram are insomnia (14% vs. 4% for placebo), diarrhea (15% vs. 5% for placebo), dry mouth (9% vs 3% for placebo), somnolence (9% vs 1% for placebo), dizziness (7% vs 2% for placebo), sweating (8% vs 1% for placebo), constipation (6% vs 1% for placebo), fatigue (6% vs 2% for placebo) and indigestion (6% vs. 1% for placebo).[18] Escitalopram, like other SSRIs, has been shown to affect sexual functions causing side effects such as decreased libido, ejaculatory delay, and anorgasmia.[19][20]

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).[21] 1.4–1.8 kg mean weight gain was reported in 8-month trials of escitalopram for depression,[22] and generalized anxiety disorder.[23] A 52-week trial of escitalopram for the long-term treatment of depression in elderly also found insignificant 0.6 kg mean weight gain.[24] Escitalopram may help reduce weight in those treated for binge eating associated obesity.[25]

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.[26][27][28] Similarly, the UK MHRA data indicate an 80% increase of suicide-related events, not reaching statistical significance, in the escitalopram vs placebo patients.[29] 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.[30] A single case report described a patient developing suicidal ideation after beginning treatment with escitalopram, and suicidal ideation disappearing after stopping the treatment.[31]

Escitalopram should be taken with caution when using St John's wort.[32] Exposure to escitalopram is moderately, by about 50%, increased when it is taken with omeprazole. The authors of this study, employed by Lundbeck, suggested that this increase is unlikely to be of clinical concern[33]

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, acute depressions and irritability.[34]

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.[35]

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 non-practicing physician named Joseph Piacentile, and the other by a Forest salesman named Christopher Gobble who was disturbed at what he witnessed at Forest.[36]

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 is illegal for a manufacturer to 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.[37][38] 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.[39]"

References

  1. ↑ "2000 Annual Report. p 28 and 33" (PDF). Lundbeck. 2000. http://www.materials.lundbeck.com/lundbeck/82/fullpdf/1.pdf. Retrieved 2007-04-07. 
  2. ↑ "New drugs from old. Presented at the Medical Journal Club, Morriston Hospital by Scott Pegler, Pharmacist at the National Health Service (UK) on November 20, 2006" (PPT). http://www.pharmedout.org/Pegler_New_Drugs_From_Old_Nov2006.ppt. Retrieved 2007-04-07. 
  3. ↑ "New drugs from old". Drug and Therapeutics Bulletin ;44:73-77; (BMJ Publishing Group Ltd.) 44: 73–77. 2006. doi:10.1136/dtb.2006.441073. http://dtb.bmj.com/cgi/content/abstract/44/10/73?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=escitalopram&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT. 
  4. ↑ Miranda Hitti. "FDA OKs Generic Depression Drug – Generic Version of Lexapro Gets Green Light". WebMD. http://www.webmd.com/content/article/122/114778.htm. Retrieved 2007-10-10. 
  5. ↑ Marie-Eve Laforte (2006-07-14). "US court upholds Lexapro patent". FirstWord. http://www.firstwordplus.com/Fws.do?src=corp_site&articleid=7474B41ED0D14C20894E262219E24B62. Retrieved 2007-10-10. 
  6. ↑ PRNewswire-FirstCall (2006-03-02). "Forest Laboratories Receives Patent Term Extension for Lexapro". Press release. http://www.frx.com/news/PressRelease.aspx?ID=824655. Retrieved 2009-01-19. 
  7. ↑ Moore N, Verdoux H, Fantino B (2005). "Prospective, multicentre, randomized, double-blind study of the efficacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder". International Clinical Psychopharmacology 20 (3): 131–137. doi:10.1097/00004850-200505000-00002. PMID 15812262. 
  8. ↑ Boulenger JP, Huusom AK, Florea I, Baekdal T, Sarchiapone M (2006). "A comparative study of the efficacy of long-term treatment with escitalopram and paroxetine in severely depressed patients". Current Medical Research and Opinion 22 (7): 1331–41. doi:10.1185/030079906X115513. PMID 16834832. 
  9. ↑ Lam RW, Andersen HF, Wade AG (July 2008). "Escitalopram and duloxetine in the treatment of major depressive disorder: a pooled analysis of two trials". Int Clin Psychopharmacol 23 (4): 181–87. doi:10.1097/YIC.0b013e3282ffdedc. PMID 18545055. 
  10. ↑ Bielski RJ, Ventura D, Chang CC (2004). "A double-blind comparison of escitalopram and venlafaxine extended release in the treatment of major depressive disorder". The Journal of Clinical Psychiatry 65 (9): 1190–96. PMID 15367045. 
  11. ↑ Ventura D, Armstrong EP, Skrepnek GH, Haim Erder M (2007). "Escitalopram versus sertraline in the treatment of major depressive disorder: a randomized clinical trial". Current Medical Research and Opinion 23 (2): 245–50. doi:10.1185/030079906X167273. PMID 17288677. 
  12. ↑ "Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis", Andrea Cipriani, Toshiaki A Furukawa, Georgia Salanti, John R Geddes, et al. The Lancet , Published Online, January 29, 2009, DOI:10.1016/S0140-6736(09)60046-5
  13. ↑ Zoloft, Lexapro the Best of Newer Antidepressants, HealthDay News, Washington Post, January 29, 2009
  14. ↑ Escitalopram Dose
  15. ↑ For an overview of supporting data, see Sánchez C, Bøgesø KP, Ebert B, Reines EH, Braestrup C (2004). "Escitalopram versus citalopram: the surprising role of the R-enantiomer". Psychopharmacology (Berl.) 174 (2): 163–76. doi:10.1007/s00213-004-1865-z. PMID 15160261. 
  16. ↑ Chen F, Larsen MB, Sánchez C, Wiborg O (2005). "The S-enantiomer of R,S-citalopram, increases inhibitor binding to the human serotonin transporter by an allosteric mechanism. Comparison with other serotonin transporter inhibitors". European Neuropsychopharmacology 15 (2): 193–198. doi:10.1016/j.euroneuro.2004.08.008. PMID 15695064. 
  17. ↑ Mansari ME, Wiborg O, Mnie-Filali O, Benturquia N, Sánchez C, Haddjeri N (2007). "Allosteric modulation of the effect of escitalopram, paroxetine and fluoxetine: in-vitro and in-vivo studies". The International Journal of Neuropsychopharmacology 10 (1): 31–40. doi:10.1017/S1461145705006462. PMID 16448580. 
  18. ↑ FDA Center for Drug Evaluation and Research (2001). "Review and evaluation of clinical data for application 21-323". http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-323.pdf_Lexapro_Medr_P1.pdf. Retrieved 2009-12-03. 
  19. ↑ Clayton A, Keller A, McGarvey EL (2006). "Burden of phase-specific sexual dysfunction with SSRIs". Journal of Affective Disorders 91 (1): 27–32. doi:10.1016/j.jad.2005.12.007. PMID 16430968. 
  20. ↑ Lexapro prescribing information
  21. ↑ Baldwin DS, Reines EH, Guiton C, Weiller E (2007). "Escitalopram therapy for major depression and anxiety disorders". Ann Pharmacother 41 (10): 1583–92. doi:10.1345/aph.1K089. PMID 17848424. 
  22. ↑ Pigott TA, Prakash A, Arnold LM, Aaronson ST, Mallinckrodt CH, Wohlreich MM (2007). "Duloxetine versus escitalopram and placebo: an 8-month, double-blind trial in patients with major depressive disorder". Curr Med Res Opin 23: 1303. doi:10.1185/030079907X188107. PMID 17559729. 
  23. ↑ Davidson JR, Bose A, Wang Q (2005). "Safety and efficacy of escitalopram in the long-term treatment of generalized anxiety disorder". J Clin Psychiatry 66 (11): 1441–6. PMID 16420082. 
  24. ↑ Kasper S, Lemming OM, de Swart H (2006). "Escitalopram in the long-term treatment of major depressive disorder in elderly patients". Neuropsychobiology 54 (3): 152–9. doi:10.1159/000098650. PMID 17230032. 
  25. ↑ Guerdjikova, Anna I.; Susan L. McElroy, Renu Kotwal, Jeffrey A. Welge, Erik Nelson, Katie Lake, David D' Alessio, Paul E. Keck Jr, James I. Hudson (2008). "High-dose escitalopram in the treatment of binge-eating disorder with obesity: a placebo-controlled monotherapy trial". Human Psychopharmacology: Clinical and Experimental 23 (1): 1–11. doi:10.1002/hup.899. PMID 18058852. 
  26. ↑ Levenson M, Holland C. "Antidepressants and Suicidality in Adults: Statistical Evaluation. (Presentation at Psychopharmacologic Drugs Advisory Committee; December 13, 2006)". http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4272s1-04-FDA.ppt. Retrieved 2007-05-13. 
  27. ↑ Stone MB, Jones ML (2006-11-17). "Clinical Review: Relationship Between Antidepressant Drugs and Suicidality in Adults" (PDF). Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC). FDA. pp. 11–74. http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf. Retrieved 2007-09-22. 
  28. ↑ Levenson M, Holland C (2006-11-17). "Statistical Evaluation of Suicidality in Adults Treated with Antidepressants" (PDF). Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC). FDA. pp. 75–140. http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf. Retrieved 2007-09-22. 
  29. ↑ Gunnell D, Saperia J, Ashby D (2005). "Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trials submitted to the MHRA's safety review". BMJ 330 (7488): 385. doi:10.1136/bmj.330.7488.385. PMID 15718537. 
  30. ↑ Khan A, Schwartz K (2007). "Suicide risk and symptom reduction in patients assigned to placebo in duloxetine and escitalopram clinical trials: analysis of the FDA summary basis of approval reports". Ann Clin Psychiatry 19 (1): 31–6. doi:10.1080/10401230601163550. PMID 17453659. 
  31. ↑ Budur, Kumar; Jeffrey Hutzler (June 2004). "Severe suicidal ideation with escitalopram (Lexapro): a case report". Primary Care Psychiatry 9 (2): 67–68. doi:10.1185/135525704125004222. 
  32. ↑ Karch, Amy (2006). 2006 Lippincott's Nursing Drug Guide. Philadephia, Baltimore, New York, London, Buenos Aires, Hong Kong, Sydney, Tokyo: Lippincott Williams & Wilkins. ISBN 1-58255-436-6. 
  33. ↑ PMID 16120067 (PubMed)
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  34. ↑ "Lexapro – Warnings". RxList. 12/08/2004. http://www.rxlist.com/cgi/generic/lexapro_wcp.htm. Retrieved 2006-10-22. 
  35. ↑ Harris, "A Drug Maker’s Playbook Reveals a Marketing Strategy"
  36. ↑ "Forest Laboratories: A Tale of Two Whistleblowers" article by Alison Frankel in The American Lawyer February 27, 2009
  37. ↑ United States of America v. Forest Laboratories Full text of the federal complaint filed in the US District Court for the district of Massachusetts
  38. ↑ "Drug Maker Is Accused of Fraud" article by Barry Meier and Benedict Carey in The New York Times February 25, 2009
  39. ↑ "Forest Laboratories, Inc. Provides Statement in Response to Complaint Filed by U.S. Government" Forest press-release. February 26, 2009

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