Escitalopram
201304
224105591
2008-07-07T09:49:01Z
Paul gene
3683516
[[WP:UNDO|Undid]] revision 224091750 by [[Special:Contributions/93.108.120.116|93.108.120.116]] ([[User talk:93.108.120.116|talk]])
{{drugbox |
| IUPAC_name = S-(+)-1-[3-(dimethylamino)propyl]-<BR>1-(''p''-fluorophenyl)-<BR>5-phthalancarbonitrileoxalate
| image = Escitalopram structure.svg
| image2 = Escitalopram-from-xtal-3D-balls.png
| width = 200
| CAS_number = 128196-01-0
| ATC_prefix = N06
| ATC_suffix = AB10
| PubChem = 146570
| DrugBank = APRD00683
| C=20 | H=21 | F=1 | N=2 | O=1
| molecular_weight = 324.392 g/mol<br>(414.40 as oxalate)
| smiles = N#Cc1ccc2c(COC2(CCCN(C)C)c2ccc(F)cc2)c1
| bioavailability = 80%
| protein_bound = ~56%
| metabolism = Liver, specifically the enzymes [[CYP3A4]] and [[CYP2C19]]
| elimination_half-life = 27–32 hours
| excretion =
| pregnancy_category = C
| legal_status = Rx-only
| routes_of_administration = Oral
}}
'''Escitalopram''' (trade names '''Lexapro''', '''Cipralex''') is the pure (S) [[enantiomer]] of [[citalopram]] and is a [[selective serotonin reuptake inhibitor]] (SSRI). Escitalopram is used in the treatment of [[Major depressive disorder|depression]] and [[anxiety]].
==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 [[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.<ref>{{cite web | title=2000 Annual Report. p 28 and 33 | url=http://www.materials.lundbeck.com/lundbeck/82/fullpdf/1.pdf |format=PDF |date=2000 |publisher=Lundbeck | accessdate=2007-04-07}}</ref>
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 "lifecycle management"<ref>{{cite web | title=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| url=http://www.pharmedout.org/Pegler_New_Drugs_From_Old_Nov2006.ppt |format=PPT |accessdate=2007-04-07}}</ref> - the strategy pharmaceutical companies use in order to extend the lifetime of a drug, in this case of the citalopram franchise. Escitalopram is an [[enantiomer]] of [[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.<ref>{{cite news |author=Miranda Hitti |title=FDA OKs Generic Depression Drug -- Generic Version of Lexapro Gets Green Light |url=http://www.webmd.com/content/article/122/114778.htm |publisher=WebMD |accessdate=2007-10-10}}</ref> However, on [[July 14]] of that year, the [[United States District Court for the District of Delaware|U.S. District Court of Delaware]] decided in favor of Lundbeck regarding the patent infringement dispute and ruled the patent on escitalopram valid.<ref>{{cite news |author=Marie-Eve Laforte |title= US court upholds Lexapro patent |date=2006-07-14 |url=http://www.firstwordplus.com/Fws.do?src=corp_site&articleid=7474B41ED0D14C20894E262219E24B62 |publisher=FirstWord |accessdate=2007-10-10}}</ref>
Despite the drug's similarity, preclinical as well as various clinical studies (including [[Blind experiment|double-blinded studies]]) have shown differentiated effects of citalopram and escitalopram,<ref name="pmid15812262">{{cite journal
|author=Moore N, Verdoux H, Fantino B
|title=Prospective, multicentre, randomized, double-blind study of the efficacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder
|journal=International Clinical Psychopharmacology
|volume=20
|issue=3
|pages=131–137
|year=2005
|pmid=15812262
|doi=10.1097/00004850-200505000-00002
}}</ref>
as well as a clinical superiority compared with a variety of other SSRIs, such as [[paroxetine]],<ref name="pmid16834832">{{cite journal
|author=Boulenger JP, Huusom AK, Florea I, Baekdal T, Sarchiapone M
|title=A comparative study of the efficacy of long-term treatment with escitalopram and paroxetine in severely depressed patients
|journal=Current Medical Research and Opinion
|volume=22
|issue=7
|pages=1331–41
|year=2006
|pmid=16834832
|doi=10.1185/030079906X115513
}}</ref> especially in severely depressed patients, and [[sertraline]]. Compared with newer [[serotonin-norepinephrine reuptake inhibitor]]s such as [[venlafaxine]]<ref name="pmid15367045">{{cite journal
|author=Bielski RJ, Ventura D, Chang CC
|title=A double-blind comparison of escitalopram and venlafaxine extended release in the treatment of major depressive disorder
|journal=The Journal of Clinical Psychiatry
|volume=65
|issue=9
|pages=1190–1196
|year=2004
|pmid=15367045
|doi=
}}</ref> and [[duloxetine]]<ref name="pmid17288694">{{cite journal
|author=Nierenberg AA, Greist JH, Mallinckrodt CH, ''et al''
|title=Duloxetine versus escitalopram and placebo in the treatment of patients with major depressive disorder: onset of antidepressant action, a non-inferiority study
|journal=Current Medical Research and Opinion
|volume=23
|issue=2
|pages=401–416
|year=2007
|pmid=17288694
|doi=10.1185/030079906X167453
}}</ref>
escitalopram was shown to be at least as effective.
==Pharmacology==
'''Escitalopram''' ('''Lexapro''' by [[Forest Laboratories]] in the United States and elsewhere by [[Lundbeck]] as '''Cipralex''', '''Sipralexa''' and '''Seroplex''')<ref>{{cite web |title=Cipralex |url=http://www.lundbeck.com/products/our_products/cipralex/default.asp |publisher=Lundbeck |accessdate=2008-01-03}}</ref>
is an [[antidepressant]] of the [[selective serotonin reuptake inhibitor]] (SSRI) class. It is approved for the treatment of [[major depressive disorder]] and [[generalized anxiety disorder]]; 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 ''es''citalopram. 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.<ref name="pmid15014731">{{cite journal |author=Burke WJ, Kratochvil CJ |title=Stereoisomers in Psychiatry: The Case of Escitalopram |journal=Prim Care Companion J Clin Psychiatry |volume=4 |issue=1 |pages=20–24 |year=2002 |pmid=15014731 |doi= |url=http://www.psychiatrist.com/pcc/pccpdf/v04n01/v04n0107.pdf |format=PDF}}</ref>
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.<ref name="pmid15160261">For the overview of supporting data, see {{cite journal
|author=Sánchez C, Bøgesø KP, Ebert B, Reines EH, Braestrup C
|title=Escitalopram versus citalopram: the surprising role of the R-enantiomer
|journal=Psychopharmacology (Berl.)
|volume=174
|issue=2
|pages=163–76
|year=2004
|pmid=15160261
|doi=10.1007/s00213-004-1865-z
}}</ref>
Further research by the same group showed that ''R''-citalopram also enhances binding of escitalopram,<ref name="pmid15695064">{{cite journal
|author=Chen F, Larsen MB, Sánchez C, Wiborg O
|title=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
|journal=European Neuropsychopharmacology
|volume=15
|issue=2
|pages=193–198
|year=2005
|pmid=15695064
|doi=10.1016/j.euroneuro.2004.08.008
}}</ref> and therefore the allosteric interaction cannot explain the observed counteracting effect. However, in the most recent paper the same authors again reversed their findings and reported that ''R''-citalopram decreases binding of escitalopram to the transporter.<ref name="pmid16448580">{{cite journal
|author=Mansari ME, Wiborg O, Mnie-Filali O, Benturquia N, Sánchez C, Haddjeri N
|title=Allosteric modulation of the effect of escitalopram, paroxetine and fluoxetine: in-vitro and in-vivo studies
|journal= The International Journal of Neuropsychopharmacology
|volume=10
|issue=1
|pages=31–40
|year=2007
|pmid=16448580
|doi=10.1017/S1461145705006462
}}</ref> 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==
[[Image:Lexapro pills.jpg|thumb|right|250px|Lexapro tablets]]
[[Image:Cipralex.jpg|thumb|right|250px|Cipralex brand escitalopram package and tablet sheet]]
{{main|Selective serotonin reuptake inhibitor}}
The [[Adverse drug reaction|side effect]] profile of escitalopram is close to that of other [[SSRI]]s, with nausea, [[somnolence]], and gastrointestinal side effects reported as relatively common. Escitalopram, like other SSRIs<ref name="pmid16430968">{{cite journal
|author=Clayton A, Keller A, McGarvey EL
|title=Burden of phase-specific sexual dysfunction with SSRIs
|journal=Journal of Affective Disorders
|volume=91
|issue=1
|pages=27–32
|year=2006
|pmid=16430968
|doi=10.1016/j.jad.2005.12.007
}}</ref>, has been shown to cause [[sexual]] side effects in many patients.
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).<ref name="pmid17848424">{{cite journal |author=Baldwin DS, Reines EH, Guiton C, Weiller E |title=Escitalopram therapy for major depression and anxiety disorders |journal=Ann Pharmacother |volume=41 |issue=10 |pages=1583–92 |year=2007 |pmid=17848424 |doi=10.1345/aph.1K089}}</ref> 1.4-1.8 kg mean weight gain was reported in 8-month trials of escitalopram for depression,<ref name="pmid17559729">{{cite journal |author=Pigott TA, Prakash A, Arnold LM, Aaronson ST, Mallinckrodt CH, Wohlreich MM |title=Duloxetine versus escitalopram and placebo: an 8-month, double-blind trial in patients with major depressive disorder |journal=Curr Med Res Opin |volume= 23|issue= |pages=1303|year=2007 |pmid=17559729 |doi=10.1185/030079907X188107}}</ref> and [[generalized anxiety disorder]].<ref name="pmid16420082">{{cite journal |author=Davidson JR, Bose A, Wang Q |title=Safety and efficacy of escitalopram in the long-term treatment of generalized anxiety disorder |journal=J Clin Psychiatry |volume=66 |issue=11 |pages=1441–6 |year=2005 |pmid=16420082 |doi=}}</ref> A 52-week trial of escitalopram for the long-term treatment of depression in elderly also found insignificant 0.6 kg mean weight gain.<ref name="pmid17230032">{{cite journal |author=Kasper S, Lemming OM, de Swart H |title=Escitalopram in the long-term treatment of major depressive disorder in elderly patients |journal=Neuropsychobiology |volume=54 |issue=3 |pages=152–9 |year=2006 |pmid=17230032 |doi=10.1159/000098650}}</ref> Escitalopram may help reduce weight in those treated for [[binge eating]] associated [[obesity]].<ref name="pmid18058852">{{cite journal
| last = Guerdjikova
| first = Anna I.
| coauthors = Susan L. McElroy, Renu Kotwal, Jeffrey A. Welge, Erik Nelson, Katie Lake, David D' Alessio, Paul E. Keck Jr, James I. Hudson
|title = High-dose escitalopram in the treatment of binge-eating disorder with obesity: a placebo-controlled monotherapy trial
|journal= Human Psychopharmacology: Clinical and Experimental
|volume=23
|issue=1
|pages=1–11
|year=2008
|pmid=18058852
|doi=10.1002/hup.899
}}</ref>
It may also cause dizziness after exercise in children.{{Fact|date=December 2007}}
A meta-analysis of clinical trials database conducted by the escitalopram manufacturer Lundbeck found no indication that escitalopram would provoke suicidal behaviour compared with [[placebo]] in patients with [[major depressive disorder]] and [[anxiety disorder]]s, on the contrary, suicidal thoughts in the escitalopram group were significantly decreased.<ref name="pmid15812263">{{cite journal
| author=Pedersen AG
| title=Escitalopram and suicidality in adult depression and anxiety
| journal= International Clinical Psychopharmacology
| volume=20
| issue=3
| pages=139–143
| year=2005
| pmid=15812263
| doi=10.1097/00004850-200505000-00003
}}</ref> 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.<ref name=FDA>{{cite web | author = Levenson M, Holland C| title =Antidepressants and Suicidality in Adults: Statistical Evaluation. (Presentation at Psychopharmacologic Drugs Advisory Committee; December 13, 2006)|accessdate = 2007-05-13 | url = http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4272s1-04-FDA.ppt}}</ref><ref name =FDA2>{{cite web | url = http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | title = CLINICAL REVIEW: RELATIONSHIP BETWEEN ANTIDEPRESSANT DRUGS AND SUICIDALITY IN ADULTS| accessdate = 2007-09-22 | author = Stone MB, Jones ML | authorlink = | coauthors = |date=2006-11-17| format =PDF | work = Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC) | publisher = FDA| pages = 11-74| language = | archiveurl = | archivedate = | quote = }}</ref><ref name =FDA3>{{cite web | url = http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | title = Statistical Evaluation of Suicidality in Adults Treated with Antidepressants | accessdate = 2007-09-22 | author = Levenson M, Holland C | authorlink = | coauthors = |date=2006-11-17| format =PDF | work =Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC) | publisher = FDA| pages = 75-140| language = | archiveurl = | archivedate = | quote = }}</ref> Similarly, the UK [[MHRA]] data indicate an 80% increase of suicide-related events, not reaching statistical significance, in the escitalopram vs placebo patients.<ref name="pmid15718537">{{cite journal |author=Gunnell D, Saperia J, Ashby D |title=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 |journal=BMJ |volume=330 |issue=7488 |pages=385 |year=2005 |pmid=15718537 |doi=10.1136/bmj.330.7488.385|accessdate=2007-09-25}}</ref> 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.<ref name="pmid17453659">{{cite journal |author=Khan A, Schwartz K |title=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 |journal=Ann Clin Psychiatry |volume=19 |issue=1 |pages=31–6 |year=2007 |pmid=17453659 |doi=10.1080/10401230601163550}}</ref> A single [[case report]] described a patient developing [[suicidal ideation]] after beginning treatment with escitalopram, and suicidal ideation disappearing after stopping the treatment.<ref>{{Cite journal
| last = Budur
| first = Kumar
| coauthors = Jeffrey Hutzler
| title = Severe suicidal ideation with escitalopram (Lexapro): a case report
| journal = Primary Care Psychiatry
| volume = 9
| issue = 2
| month = June
| year= 2004
| pages = 67–68
| doi = 10.1185/135525704125004222
}}</ref>
Escitalopram should be taken with caution when using [[St John's wort]].<ref>{{cite book | title=2006 Lippincott's Nursing Drug Guide |last=Karch |first=Amy |year= 2006 |publisher=Lippincott Williams & Wilkins |location=Philadephia, Baltimore, New York, London, Buenos Aires, Hong Kong, Sydney, Tokyo |isbn= 1-58255-436-6 }}</ref>
==Discontinuation symptoms==
{{main|SSRI discontinuation syndrome}}
Lexapro discontinuation, particularly abruptly, may cause certain [[Withdrawal#Withdrawal_from_prescription_medicine|withdrawal]] [[symptom]]s such as [[paresthesia]] (for example, electric shock sensations also known as "[[brain zaps|brain shivers]]" or "[[brain zaps]]"), [[dizziness]] and [[irritability]].<ref>{{cite web | title=Lexapro -- Warnings | url=http://www.rxlist.com/cgi/generic/lexapro_wcp.htm |date=12/08/2004 | publisher=RxList | accessdate=2006-10-22}}</ref>
==Footnotes==
{{reflist|2}}
== External links ==
* [http://www.lexapro.com/ Lexapro (Forest Laboratories)] Official Lexapro Homepage
* [http://www.cipralex.com/ Cipralex (Lundbeck)] Official Cipralex Homepage
* [http://www.rxlist.com/cgi/generic/lexapro.htm Pharmacological information] Lexapro
{{Antidepressants}}
<!--Categories-->
[[Category:Selective serotonin reuptake inhibitors]]
[[Category:Nitriles]]
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