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Escitalopram oxalate

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Escitalopram oxalate chemical structure
Escitalopram oxalate

S-(+)-1-[3-(dimethylamino)propyl]-
1-(p-fluorophenyl)-
5-phthalancarbonitrileoxalate
IUPAC name
CAS number
128196-01-0
ATC code

N06AB10

PubChem
146570
DrugBank
APRD00683
Chemical formula {{{chemical_formula}}}
Molecular weight 324.392 g/mol
(414.40 as oxalate)
Bioavailability 80%
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
Lexapro pills

Lexapro pills

Cipralex

Cipralex brand escitalopram package and pill sheet

Escitalopram (Lexapro by Forest Laboratories in the United States and elsewhere by Lundbeck as Cipralex, Sipralexa and Seroplex)[1] 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 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.[2]

HistoryEdit

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.[3] 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"[4] - 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.[5] However, on July 14 of that year, the U.S. District Court of Delaware decided in favor of Lundbeck regarding the patent infringement dispute and ruled the patent on escitalopram valid.[6]

Despite the drug's similarity, 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 and sertraline. Compared with newer serotonin-norepinephrine reuptake inhibitors such as venlafaxine[9] and duloxetine[10] escitalopram was shown to be at least as effective.

PharmacologyEdit

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). Remarkably, 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.[11] Further research by the same group showed that R-citalopram also enhances binding of escitalopram,[12] 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.[13] 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 interactionsEdit

Main article: Selective serotonin reuptake inhibitor

The side effect profile of escitalopram is close to that of other SSRIs, with nausea, somnolence, and gastrointestinal side effects reported as relatively common. Escitalopram, like other SSRIs, has been shown to cause sexual side effects in many patients.[14] 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).[15] 1.4-1.8 kg mean weight gain was reported in 8-month trials of escitalopram for depression,[16] and generalized anxiety disorder.[17] A 52-week trial of escitalopram for the long-term treatment of depression in elderly also found insignificant 0.6 kg mean weight gain.[18] Escitalopram may help reduce weight in those treated for binge eating associated obesity.[19] It may also cause dizziness after exercise in children.[How to reference and link to summary or text]

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 disorders, on the contrary, suicidal thoughts in the escitalopram group were significantly decreased.[20] 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.[21][22][23] Similarly, the UK MHRA data indicate an 80% increase of suicide-related events, not reaching statistical significance, in the escitalopram vs placebo patients.[24] 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.[25] A single case report described a patient developing suicidal ideation after beginning treatment with escitalopram, and suicidal ideation disappearing after stopping the treatment.[26]

Escitalopram should be taken with caution when using St John's wort.[27]

Discontinuation symptomsEdit

Main article: SSRI discontinuation syndrome

Lexapro discontinuation, particularly abruptly, may cause certain withdrawal symptoms such as paresthesia (for example, electric shock sensations also known as "brain shivers" or "brain zaps"), dizziness and irritability.[28]

FootnotesEdit

  1. Cipralex. Lundbeck. URL accessed on 2008-01-03.
  2. Burke WJ, Kratochvil CJ (2002). Stereoisomers in Psychiatry: The Case of Escitalopram. Prim Care Companion J Clin Psychiatry 4 (1): 20–24.
  3. 2000 Annual Report. p 28 and 33. (PDF) Lundbeck. URL accessed on 2007-04-07.
  4. 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) URL accessed on 2007-04-07.
  5. includeonly>Miranda Hitti. "FDA OKs Generic Depression Drug -- Generic Version of Lexapro Gets Green Light", WebMD. Retrieved on 2007-10-10.
  6. includeonly>Marie-Eve Laforte. "US court upholds Lexapro patent", FirstWord, July 14, 2006. Retrieved on 2007-10-10.
  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.
  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.
  9. 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): 1190–1196.
  10. Nierenberg AA, Greist JH, Mallinckrodt CH, et al (2007). Duloxetine versus escitalopram and placebo in the treatment of patients with major depressive disorder: onset of antidepressant action, a non-inferiority study. Current Medical Research and Opinion 23 (2): 401–416.
  11. For the 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.
  12. 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.
  13. 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.
  14. Clayton A, Keller A, McGarvey EL (2006). Burden of phase-specific sexual dysfunction with SSRIs. Journal of Affective Disorders 91 (1): 27–32.
  15. Baldwin DS, Reines EH, Guiton C, Weiller E (2007). Escitalopram therapy for major depression and anxiety disorders. Ann Pharmacother 41 (10): 1583–92.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. Pedersen AG (2005). Escitalopram and suicidality in adult depression and anxiety. International Clinical Psychopharmacology 20 (3): 139–143.
  21. Levenson M, Holland C. Antidepressants and Suicidality in Adults: Statistical Evaluation. (Presentation at Psychopharmacologic Drugs Advisory Committee; December 13, 2006). URL accessed on 2007-05-13.
  22. Stone MB, Jones ML. CLINICAL REVIEW: RELATIONSHIP BETWEEN ANTIDEPRESSANT DRUGS AND SUICIDALITY IN ADULTS. (PDF) Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC). FDA. URL accessed on 2007-09-22.
  23. Levenson M, Holland C. Statistical Evaluation of Suicidality in Adults Treated with Antidepressants. (PDF) Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC). FDA. URL accessed on 2007-09-22.
  24. 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.
  25. 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.
  26. Budur, Kumar, Jeffrey Hutzler (June 2004). Severe suicidal ideation with escitalopram (Lexapro): a case report. Primary Care Psychiatry 9 (2): 67–68.
  27. Karch, Amy (2006). 2006 Lippincott's Nursing Drug Guide, Philadephia, Baltimore, New York, London, Buenos Aires, Hong Kong, Sydney, Tokyo: Lippincott Williams & Wilkins.
  28. Lexapro -- Warnings. RxList. URL accessed on 2006-10-22.

External links Edit



Antidepressants (ATC N06A) edit
Monoamine oxidase inhibitors (MAOI) Harmaline, Iproclozide, Iproniazid, Isocarboxazid, Nialamide, Phenelzine, Selegiline, Toloxatone, Tranylcypromine
Reversible inhibitor of monoamine oxidase A (RIMA) Brofaromine, Moclobemide
Dopamine reuptake inhibitor (DARI) Amineptine, Phenmetrazine, Vanoxerine, Modafinil
Norepinephrine-dopamine reuptake inhibitors Bupropion
Norepinephrine reuptake inhibitor (NRI) or (NARI) Atomoxetine, Maprotiline, Reboxetine, Viloxazine
Serotonin-norepinephrine reuptake inhibitor (SNRI) Duloxetine, Milnacipran, Venlafaxine
Selective serotonin reuptake inhibitor (SSRI) Alaproclate, Etoperidone, Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Zimelidine
Selective serotonin reuptake enhancer (SSRE) Tianeptine
Tricyclic antidepressants (TCA) Amitriptyline, Amoxapine, Butriptyline, Clomipramine, Desipramine, Dibenzepin, Dothiepin, Doxepin, Imipramine, Iprindole, Lofepramine, Melitracen, Nortriptyline, Opipramol, Protriptyline, Trimipramine
Tetracyclic antidepressants Maprotiline, Mianserin, Nefazodone, Trazodone
Noradrenergic and specific serotonergic antidepressant (NaSSA) Mirtazapine

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