Escitalopram

This article is about the left handed version of the drug. For its racemic form, see citalopram.
Escitalopram
Clinical data
Pronunciation  pronunciation 
Trade names Cipralex, Lexapro and many others[1]
AHFS/Drugs.com Monograph
MedlinePlus a603005
License data
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Routes of
administration		 Oral
ATC code N06AB10 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 80%
Protein binding ~56%
Metabolism Liver, specifically the enzymes CYP3A4 and CYP2C19
Biological half-life 27–32 hours
Identifiers
CAS Number 128196-01-0 YesY
PubChem (CID) 146570
DrugBank DB01175 N
ChemSpider 129277 YesY
UNII 4O4S742ANY YesY
ChEBI CHEBI:36791 YesY
ChEMBL CHEMBL1508 YesY
Chemical and physical data
Formula C20H21FN2O
Molar mass 324.392 g/mol
(414.43 as oxalate)
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

Escitalopram, also known by the brand names Lexapro and Cipralex among others, 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 adults and children over 12 years of age with major depressive disorder (MDD) or generalized anxiety disorder (GAD). Escitalopram is the (S)-stereoisomer (Left-enantiomer) of the earlier Lundbeck drug citalopram, hence the name escitalopram. Whether escitalopram exhibits superior therapeutic properties to citalopram or merely represents an example of "evergreening" is controversial.[2]

The utility of antidepressant drugs in the treatment of mild-to-moderate depression is itself controversial. In those with very severe depression there is a large benefit.[3]

Medical uses

Escitalopram has FDA approval for the treatment of major depressive disorder in adolescents and adults, and generalized anxiety disorder in adults.[4] In European countries and Australia, it is approved for depression (MDD) and certain anxiety disorders: general anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and panic disorder with or without agoraphobia.

Depression

Escitalopram was approved by regulatory authorities for the treatment of major depressive disorder on the basis of four placebo controlled, double-blind trials, three of which demonstrated a statistical superiority over placebo.[5] Nonetheless, considerable controversy exists regarding the superiority of escitalopram to its predecessor citalopram. The importance of this issue follows from the greater cost of escitalopram relative to the generic mixture of isomers citalopram prior to the expiration of the escitalopram patent in 2012, which led to charges of evergreening. Accordingly, this issue has been examined in at least 10 different systematic reviews and meta analyses. The most recent of these have concluded (with caveats in some cases) that escitalopram is modestly superior to citalopram in efficacy and/or tolerability.[6][7][8][9]

In contrast to these findings, a 2011 review concluded that all second-generation antidepressants are equally effective,[10] and treatment guidelines issued by the National Institute of Health and Clinical Excellence and by the American Psychiatric Association generally reflect this viewpoint.[11][12]

Anxiety disorder

There may be a significant improvement in GAD symptoms as early as the first week and the majority of patients respond by week eight with a significant improvement in functioning.[13] It also seems effective in the long-term, with relapse on escitalopram (20%) less than placebo (50%).[14]

Escitalopram and citalopram appear equally effective in panic disorder.[15]

Other

Escitalopram as well as other SSRIs are effective in reducing the symptoms of premenstrual syndrome, whether taken in the luteal phase only or continuously.[16] There is no good data available for escitalopram for seasonal affective disorder as of 2011.[17] SSRIs do not appear to be useful for preventing tension headaches or migraines.[18][19]

Adverse effects

Escitalopram, like other SSRIs, has been shown to affect sexual functions causing side effects such as decreased libido, delayed ejaculation, genital anesthesia,[20] and anorgasmia.[21][22]

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.[23][24][25] Similarly, the UK MHRA data indicate an 80% increase of suicide-related events, not reaching statistical significance, in the escitalopram vs. placebo patients.[26] 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.[27]

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).[28] 1.4–1.8 kg mean weight gain was reported in 8-month trials of escitalopram for depression,[29] and generalized anxiety disorder.[30] A 52-week trial of escitalopram for the long-term treatment of depression in elderly also found insignificant 0.6 kg mean weight gain.[31] Escitalopram may help reduce weight in those treated for binge eating associated obesity.[32]

Citalopram and escitalopram are associated with dose-dependent QT interval prolongation[33] and should not be used in those with congenital long QT syndrome or known pre-existing QT interval prolongation, or in combination with other medicines that prolong the QT interval. ECG measurements should be considered for patients with cardiac disease, and electrolyte disturbances should be corrected before starting treatment. In December 2011, the UK implemented new restrictions on the maximum daily doses:

Escitalopram should be taken with caution when using Saint John's wort.[36] 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.[37] Caution should be used when taking cough medicine containing dextromethorphan (DXM) as serotonin syndrome, liver damage, and other negative side effects have been reported.

Discontinuation symptoms

Escitalopram discontinuation, particularly abruptly, may cause certain withdrawal symptoms such as "electric shock" sensations[38] (also known as "brain shivers" or "brain zaps"), dizziness, acute depressions and irritability, as well as heightened senses of akathisia.[39]

Pregnancy

There is a tentative association of SSRI use during pregnancy with heart problems in the baby.[40] Their use during pregnancy should thus be balanced against that of depression.[40]

Overdose

Excessive doses of escitalopram usually cause relatively minor untoward effects such as agitation and tachycardia. However, dyskinesia, hypertonia, and clonus may occur in some cases. Plasma escitalopram concentrations are usually in a range of 20-80 μg/L in therapeutic situations and may reach 80-200 μg/L in the elderly, patients with hepatic dysfunction, those who are poor CYP2C19 metabolizers or following acute overdose. Monitoring of the drug in plasma or serum is generally accomplished using chromatographic methods. Chiral techniques are available to distinguish escitalopram from its racemate, citalopram.[41][42][43] Escitalopram seems to be less dangerous than citalopram in overdose and comparable to other SSRIs.[44]

Pharmacology

Mechanism of action

Binding profile[45]
Receptor Ki (nM)
SERT 2.5
NET 6,514
5-HT2C 2,531
α1 3,870
M1 1,242
H1 1,973

Escitalopram increases intrasynaptic levels of the neurotransmitter serotonin by blocking the reuptake of the neurotransmitter into the presynaptic neuron. Of the SSRIs currently on the market, 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.[46] The opposite enantiomer, (R)-citalopram, counteracts to a certain degree the serotonin-enhancing action of escitalopram. As a result, escitalopram has been claimed to be a more potent antidepressant than the racemic mixture, citalopram, of the two enantiomers. 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.[47] Further research by the same group showed that (R)-citalopram also enhances binding of escitalopram,[48] 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.[49] 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.

Escitalopram is a substrate of P-glycoprotein and hence P-glycoprotein inhibitors such as verapamil and quinidine may improve its blood-brain penetrability.[50] In a preclinical study in rats combining escitalopram with a P-glycoprotein inhibitor enhanced its antidepressant-like effects.[50]

Interactions

Escitalopram, similarly to other SSRIs (with the exception of fluvoxamine), inhibits CYP2D6 and hence may increase plasma levels of a number of CYP2D6 substrates such as aripiprazole, risperidone, tramadol, codeine, etc. As much of the effect of codeine is attributable to its conversion (10%) to morphine its effectiveness will be reduced by this inhibition, not enhanced.[51] As escitalopram is only a weak inhibitor of CYP2D6, analgesia from tramadol may not be affected.[52] Escitalopram can also prolong the QT interval and hence it is not recommended in patients that are concurrently on other medications that have the ability to prolong the QT interval. Being a SSRI, escitalopram should not be given concurrently with MAOIs or other serotonergic medications.[46]

History

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.[53] 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.[54] 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.[55]

In 2006 Forest Laboratories was granted an 828-day (2 years and 3 months) extension on its US patent for escitalopram.[56] 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

Allegations of illegal marketing

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.[57] 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 doctors 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.[58][59] 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."[60] 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.[61]

Brand names

Escitalopram is sold under many brand names worldwide such as Cipralex.[1]

References

  1. 1 2 drugs.com Drugs.com international: Escitalopram Page accessed April 25, 2015
  2. ↑ NHS pays millions of pounds more than it needs to for drugs, The Independent. Retrieved 05/10/2011.
  3. ↑ Fournier, JC; DeRubeis, RJ; Hollon, SD; Dimidjian, S; Amsterdam, JD; Shelton, RC; Fawcett, J (6 January 2010). "Antidepressant drug effects and depression severity: a patient-level meta-analysis.". JAMA. 303 (1): 47–53. doi:10.1001/jama.2009.1943. PMC 3712503Freely accessible. PMID 20051569.
  4. ↑ "Escitalopram Oxalate". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
  5. ↑ "www.accessdata.fda.gov" (PDF).
  6. ↑ Ramsberg J, Asseburg C, Henriksson M (2012). "Effectiveness and cost-effectiveness of antidepressants in primary care: a multiple treatment comparison meta-analysis and cost-effectiveness model". PLoS ONE. 7 (8): e42003. doi:10.1371/journal.pone.0042003. PMC 3410906Freely accessible. PMID 22876296.
  7. ↑ Cipriani A, Purgato M, Furukawa TA, Trespidi C, Imperadore G, Signoretti A, Churchill R, Watanabe N, Barbui C (2012). "Citalopram versus other anti-depressive agents for depression". Cochrane Database Syst Rev. 7: CD006534. doi:10.1002/14651858.CD006534.pub2. PMID 22786497.
  8. ↑ Favré P (February 2012). "[Clinical efficacy and achievement of a complete remission in depression: increasing interest in treatment with escitalopram]". Encephale (in French). 38 (1): 86–96. doi:10.1016/j.encep.2011.11.003. PMID 22381728.
  9. ↑ Sicras-Mainar A, Navarro-Artieda R, Blanca-Tamayo M, Gimeno-de la Fuente V, Salvatella-Pasant J (December 2010). "Comparison of escitalopram vs. citalopram and venlafaxine in the treatment of major depression in Spain: clinical and economic consequences". Curr Med Res Opin. 26 (12): 2757–64. doi:10.1185/03007995.2010.529430. PMID 21034375.
  10. ↑ Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux L, Van Noord M, Mager U, Thieda P, Gaynes BN, Wilkins T, Strobelberger M, Lloyd S, Reichenpfader U, Lohr KN (Dec 6, 2011). "Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis.". Annals of Internal Medicine. 155 (11): 772–85. doi:10.7326/0003-4819-155-11-201112060-00009. PMID 22147715.
  11. ↑ "CG90 Depression in adults: full guidance".
  12. ↑ "PsychiatryOnline | APA Practice Guidelines | Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition".
  13. ↑ Davidson JR, Bose A, Korotzer A, Zheng H (2004). "Escitalopram in the treatment of generalized anxiety disorder: double-blind, placebo controlled, flexible-dose study". Depress Anxiety. 19 (4): 234–40. doi:10.1002/da.10146. PMID 15274172.
  14. ↑ Bech P, Lönn SL, Overø KF (2010). "Relapse prevention and residual symptoms: a closer analysis of placebo-controlled continuation studies with escitalopram in major depressive disorder, generalized anxiety disorder, social anxiety disorder, and obsessive-compulsive disorder". J Clin Psychiatry. 71 (2): 121–9. doi:10.4088/JCP.08m04749blu. PMID 19961809.
  15. ↑ Stahl SM, Gergel I, Li D (2003). "Escitalopram in the treatment of panic disorder: a randomized, double-blind, placebo-controlled trial". J Clin Psychiatry. 64 (11): 1322–7. doi:10.4088/jcp.v64n1107. PMID 14658946.
  16. ↑ Marjoribanks J, Brown J, O'Brien PM, Wyatt K (Jun 7, 2013). "Selective serotonin reuptake inhibitors for premenstrual syndrome.". The Cochrane database of systematic reviews. 6: CD001396. doi:10.1002/14651858.CD001396.pub3. PMID 23744611.
  17. ↑ Thaler K, Delivuk M, Chapman A, Gaynes BN, Kaminski A, Gartlehner G (Dec 7, 2011). "Second-generation antidepressants for seasonal affective disorder.". The Cochrane database of systematic reviews (12): CD008591. doi:10.1002/14651858.CD008591.pub2. PMID 22161433.
  18. ↑ Banzi, R; Cusi, C; Randazzo, C; Sterzi, R; Tedesco, D; Moja, L (1 May 2015). "Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of tension-type headache in adults.". The Cochrane database of systematic reviews. 5: CD011681. doi:10.1002/14651858.CD011681. PMID 25931277.
  19. ↑ Moja, PL; Cusi, C; Sterzi, RR; Canepari, C (20 July 2005). "Selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headaches.". The Cochrane database of systematic reviews (3): CD002919. doi:10.1002/14651858.CD002919.pub2. PMID 16034880.
  20. ↑ Bolton JM, Sareen J, Reiss JP (2006). "Genital anesthesia persisting six years after sertraline discontinuation". J Sex Marital Ther. 32 (4): 327–30. doi:10.1080/00926230600666410. PMID 16709553.
  21. ↑ 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.
  22. ↑ Lexapro prescribing information
  23. ↑ Levenson M, Holland C. "Antidepressants and Suicidality in Adults: Statistical Evaluation. (Presentation at Psychopharmacologic Drugs Advisory Committee; December 13, 2006)". Retrieved 2007-05-13.
  24. ↑ Stone MB, Jones ML (2006-11-17). "Clinical Review: Relationship Between Antidepressant Drugs and Suicidality in Adults" (PDF). Overview for December 13 Meeting of Pharmacological Drugs Advisory Committee (PDAC). FDA. pp. 11–74. Retrieved 2007-09-22.
  25. ↑ Levenson M; Holland C (2006-11-17). "Statistical Evaluation of Suicidality in Adults Treated with Antidepressants" (PDF). Overview for December 13 Meeting of Pharmacological Drugs Advisory Committee (PDAC). FDA. pp. 75–140. Retrieved 2007-09-22.
  26. ↑ 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, randomized controlled trials submitted to the MHRA's safety review". BMJ. 330 (7488): 385. doi:10.1136/bmj.330.7488.385. PMC 549105Freely accessible. PMID 15718537.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ 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 (6): 1303–18. doi:10.1185/030079907X188107. PMID 17559729.
  30. ↑ 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. doi:10.4088/JCP.v66n1115. PMID 16420082.
  31. ↑ 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.
  32. ↑ Guerdjikova AI, McElroy SL, Kotwal R, Welge JA, Nelson E, Lake K, Alessio DD, Keck PE, Hudson JI (January 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.
  33. ↑ Castro VM, Clements CC, Murphy SN, Gainer VS, Fava M, Weilburg JB, Erb JL, Churchill SE, Kohane IS, Iosifescu DV, Smoller JW, Perlis RH (2013). "QT interval and antidepressant use: a cross sectional study of electronic health records". BMJ. 346: f288. doi:10.1136/bmj.f288. PMC 3558546Freely accessible. PMID 23360890.
  34. ↑ "Citalopram and escitalopram: QT interval prolongation—new maximum daily dose restrictions (including in elderly patients), contraindications, and warnings". Medicines and Healthcare products Regulatory Agency. December 2011. Retrieved March 5, 2013.
  35. ↑ van Gorp F, Whyte IM, Isbister GK (2009). "Clinical and ECG Effects of Escitalopram Overdose" (PDF). Annals of Emergency Medicine. 54 (3): 404–8. doi:10.1016/j.annemergmed.2009.04.016. PMID 19556032.
  36. ↑ Karch, Amy (2006). 2006 Lippincott's Nursing Drug Guide. Philadelphia, Baltimore, New York, London, Buenos Aires, Hong Kong, Sydney, Tokyo: Lippincott Williams & Wilkins. ISBN 1-58255-436-6.
  37. ↑ Malling D, Poulsen MN, Søgaard B (2005). "The effect of cimetidine or omeprazole on the pharmacokinetics of escitalopram in healthy subjects". British Journal of Clinical Pharmacology. 60 (3): 287–290. doi:10.1111/j.1365-2125.2005.02423.x. PMC 1884771Freely accessible. PMID 16120067.
  38. ↑ Prakash O, Dhar V (2008). "Emergence of electric shock-like sensations on escitalopram discontinuation". J Clin Psychopharmacol. 28 (3): 359–60. doi:10.1097/JCP.0b013e3181727534. PMID 18480703.
  39. ↑ "Lexapro (Escitalopram Oxalate) Drug Information: Warnings and Precautions - Prescribing Information at RxList". Retrieved 2015-08-09.
  40. 1 2 Gentile, S (1 July 2015). "Early pregnancy exposure to selective serotonin reuptake inhibitors, risks of major structural malformations, and hypothesized teratogenic mechanisms.". Expert opinion on drug metabolism & toxicology. 11: 1–13. doi:10.1517/17425255.2015.1063614. PMID 26135630.
  41. ↑ van Gorp F, Whyte IM, Isbister GK (2009). "Clinical and ECG effects of escitalopram overdose". Ann Emerg Med. 54 (3): 404–8. doi:10.1016/j.annemergmed.2009.04.016. PMID 19556032.
  42. ↑ Haupt D (1996). "Determination of citalopram enantiomers in human plasma by liquid chromatographic separation on a Chiral-AGP column". J. Chromatogr. B, Biomed. Appl. 685 (2): 299–305. doi:10.1016/s0378-4347(96)00177-6. PMID 8953171.
  43. ↑ Baselt RC (2008). Disposition of toxic drugs and chemicals in man (8th ed.). Foster City, Ca: Biomedical Publications. pp. 552–553. ISBN 0962652377.
  44. ↑ White N, Litovitz T, Clancy C (December 2008). "Suicidal antidepressant overdoses: a comparative analysis by antidepressant type". Journal of Medical Toxicology. 4 (4): 238–250. doi:10.1007/BF03161207. PMC 3550116Freely accessible. PMID 19031375.
  45. ↑ Owens, MJ; Knight, DL; Nemeroff, CB (1 September 2001). "Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine.". Biological Psychiatry. 50 (5): 345–50. doi:10.1016/s0006-3223(01)01145-3. PMID 11543737.
  46. 1 2 Brunton L, Chabner B, Knollman B. Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth Edition. McGraw Hill Professional; 2010.
  47. ↑ 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.
  48. ↑ 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.
  49. ↑ 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.
  50. 1 2 O'Brien FE, O'Connor RM, Clarke G, Dinan TG, Griffin BT, Cryan JF (October 2013). "P-glycoprotein inhibition increases the brain distribution and antidepressant-like activity of escitalopram in rodents". Neuropsychopharmacology. 38 (11): 2209–2219. doi:10.1038/npp.2013.120. PMID 23670590.
  51. ↑ Ali Torkamani. "Selective Serotonin Reuptake Inhibitors and CYP2D6". Medscape.com. Retrieved 14 May 2015.
  52. ↑ Noehr-Jensen, L; Zwisler, ST; Larsen, F; Sindrup, SH; Damkier, P; Brosen, K (December 2009). "Escitalopram is a weak inhibitor of the CYP2D6-catalyzed O-demethylation of (+)-tramadol but does not reduce the hypoalgesic effect in experimental pain.". Clinical pharmacology and therapeutics. 86 (6): 626–33. doi:10.1038/clpt.2009.154. PMID 19710642.
  53. ↑ "2000 Annual Report. p 28 and 33" (PDF). Lundbeck. 2000. Retrieved 2007-04-07.
  54. ↑ Miranda Hitti. "FDA OKs Generic Depression Drug – Generic Version of Lexapro Gets Green Light". WebMD. Retrieved 2007-10-10.
  55. ↑ Marie-Eve Laforte (2006-07-14). "US court upholds Lexapro patent". FirstWord. Retrieved 2007-10-10.
  56. ↑ "Forest Laboratories Receives Patent Term Extension for Lexapro" (Press release). PRNewswire-FirstCall. 2006-03-02. Retrieved 2009-01-19.
  57. ↑ "Forest Laboratories: A Tale of Two Whistleblowers" article by Alison Frankel in The American Lawyer February 27, 2009
  58. ↑ United States of America v. Forest Laboratories Full text of the federal complaint filed in the US District Court for the district of Massachusetts
  59. ↑ "Drug Maker Is Accused of Fraud" article by Barry Meier and Benedict Carey in The New York Times February 25, 2009
  60. ↑ "Forest Laboratories, Inc. Provides Statement in Response to Complaint Filed by U.S. Government" Forest press-release. February 26, 2009.
  61. ↑ "US Department of Justice Press-release. September 15, 2010"

Cited texts

Further reading

External links

This article is issued from Wikipedia - version of the 11/3/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.