Escitalopram

The Cipralex brand name should not be confused with the antibiotic drug ciprofloxacin or its various brand names such as Cipro. Furthermore, the active pharmaceutical ingredient escitalopram should not be confused with citalopram, another antidepressant.

Escitalopram

Clinical data
Trade names	Lexapro
AHFS/Drugs.com	Monograph
MedlinePlus	a603005
License data	US FDA: Lexapro
Pregnancy category	AU: C
Routes of administration	Oral
ATC code	N06AB10 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: WARNINGRx-only
Pharmacokinetic data
Bioavailability	80%
Protein binding	~56%
Metabolism	Liver, specifically the enzymes CYP3A4 and CYP2C19
Elimination half-life	27–32 hours
Identifiers
IUPAC name (S)-1-[3-(Dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile
CAS Number	128196-01-0 Y
PubChem CID	146570
DrugBank	DB01175 N
ChemSpider	129277 Y
UNII	4O4S742ANY
ChEBI	CHEBI:36791 Y
ChEMBL	ChEMBL1508 Y
CompTox Dashboard (EPA)	DTXSID8048440
ECHA InfoCard	100.244.188
Chemical and physical data
Formula	C20H21FN2O
Molar mass	324.392 g/mol (414.43 as oxalate) g·mol−1
3D model (JSmol)	Interactive image
SMILES Fc1ccc(cc1)[C@@]3(OCc2cc(C#N)ccc23)CCCN(C)C
InChI InChI=1S/C20H21FN2O/c1-23(2)11-3-10-20(17-5-7-18(21)8-6-17)19-9-4-15(13-22)12-16(19)14-24-20/h4-9,12H,3,10-11,14H2,1-2H3/t20-/m0/s1 Y Key:WSEQXVZVJXJVFP-FQEVSTJZSA-N Y
NY (what is this?)  (verify)

Escitalopram (also known under various trade names such as Lexapro (AU, HK, IE, MX, NZ, PH, SG, US), Cipralex (CA, IL, ZA, UK)) 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) and generalized anxiety disorder (GAD). Escitalopram is the (S)-stereoisomer (enantiomer) of the earlier Lundbeck drug citalopram, hence the name escitalopram. The similarity between escitalopram and citalopram has led to accusations of "evergreening", an accusation that Lundbeck has rejected.

Independent analysis has found all SSRIs to be more or less equivalent in benefits. When both published and unpublished trials are taken into account the benefit appears to be little to none in those with mild or moderate depression.

Medical uses

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

Depression

There are concerns regarding selective publishing of SSRI clinical trials. A meta-analysis which looked at both published and unpublished trials found placebos to be similarly effective to SSRIs in treating mild on moderate depression, although SSRIs were more effective than placebo in more severe cases, with the magnitude of SSRI superiority increasing with increasing depression severity.

A 2011 review concluded that all second generation antidepressants are equally effective and a 2010 review did not find evidence to support escitalopram being better than citalopram.

A 2009 Cochrane review found some evidence favoring escitalopram over the antidepressants citalopram and fluoxetine in the first two weeks of major depression as did another 2009 review. There were however concerns of sponsorship bias and publication bias. In another review escitalopram and sertraline had the highest rate of efficacy and acceptability among adults receiving treatment for major depression with second-generation antidepressants, with escitalopram fairing slightly (but not statistically significantly) better than sertraline in both regards. There is no evidence for differential speed of onset of action from SSRIs overall or escitalopram specifically.

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. It also seems effective in the long-term with relapse on escitalopram (20%) less than placebo (50%).

Escitalopram and citalopram appear equally effective in panic disorder.

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. There is no good data available for escitalopram for seasonal affective disorder as of 2011.

Adverse effects

Adverse effects by incidence
Very common (>10% incidence) adverse effects include:

• Headache
• Nausea

Common (1-10% incidence) adverse effects include:

• Insomnia
• Somnolence
• Dizziness
• Paraesthesia
• Tremor
• Decreased appetite
• Increased appetite
• Weight gain
• Anxiety
• Restlessness
• Abnormal dreams
• Libido decreased
• Anorgasmia
• Sinusitis
• Yawning
• Diarrhoea
• Constipation
• Vomiting
• Dry mouth
• Excessive sweating
• Arthralgia (joint pain)
• Myalgia (muscular aches and pains)

• Fatigue
• Pyrexia (fever)
• Ejaculation disorder,
• Impotence (erectile dysfunction)

Uncommon (0.1-1% incidence) adverse effects include:

• Weight loss
• Bruxism (teeth grinding)
• Agitation
• Nervousness
• Panic attack
• Confusional state
• Taste disturbance
• Sleep disorder
• Syncope (fainting)
• Mydriasis
• Visual disturbance
• Tinnitus (hearing ringing in the ears)
• Tachycardia (high heart rate)
• Epistaxis (nosebleed)
• Gastrointestinal haemorrhages (including rectal haemorrhage)
• Urticaria (hives)
• Alopecia (hair loss)
• Rash
• Pruritus (itching)
• Metrorrhagia
• Menorrhagia (excessive menstrual bleeding)
• Oedema (accumulation of fluids in the tissues of the body)

Rare (<0.1% incidence) adverse effects include:

• Anaphylactic reaction (a potentially life-threatening allergic reaction)
• Serotonin syndrome a potentially fatal complication of excess serotonin in the nervous system leading to diaphoresis (profuse sweating), tremor, tachycardia, diarrhoea, shivering, hyperreflexia (overactive reflexes), mental status changes (e.g. confusion, hypomania, agitation), etc.
• Aggression
• Depersonalisation
• Hallucination
• Bradycardia

Unknown incidence adverse effects include:

• Thrombocytopenia
• Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
• Hyponatraemia (low blood sodium)
• Mania (a dangerously elated or irritable mood)
• Suicidal ideation
• Suicidal behaviour
• Dyskinesia
• Movement disorder
• Convulsion
• Psychomotor restlessness/akathisia
• Electrocardiogram QT prolonged (an abnormality in the heart's electrical cycle)
• Ventricular arrhythmia including torsade de pointes
• Orthostatic hypotension (a drop in blood pressure that occurs upon standing up)
• Hepatitis (liver swelling)
• Liver function test abnormal
• Ecchymosis (bruising without a physiologic reason)
• Angioedemas
• Urinary retention (being unable to urinate)
• Galactorrhoea (lactation that is not associated with breastfeeding and pregnancy)
• Priapism (a painful, prolonged erection)

Escitalopram, like other SSRIs, has been shown to affect sexual functions causing side effects such as decreased libido, delayed ejaculation, genital anesthesia, and anorgasmia. Although usually reversible upon discontinuation, these sexual side effects can last for months or years or be permanent after the drug has been completely withdrawn. This is known as post SSRI sexual dysfunction.

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

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

Citalopram and escitalopram are associated with dose-dependent QT interval prolongation 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. For citalopram, new restrictions on the maximum daily doses now apply: 40 mg for adults; 20 mg for patients older than 65 years; and 20 mg for those with hepatic impairment. For escitalopram, the maximum daily dose for patients older than 65 years is now reduced to 10 mg/day; other doses remain unchanged.

Escitalopram should be taken with caution when using Saint John's wort. Exposure to escitalopram is increased moderately, by about 50%, 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. 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

Main article: SSRI discontinuation syndrome

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, bladder control issues, as well as heightened senses of akathisia.

Human data suggests there's a risk when taking Lexapro in the third trimester of pregnancy.

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. Escitalopram seems to be less dangerous than citalopram in overdose and comparable to other SSRIs.

Drug/Food 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, codeine, etc. 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.

Pharmacology

Cipralex brand escitalopram 10mg package and tablet sheet

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 affinity for the human serotonin transporter (SERT). The enantiomer of escitalopram ((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 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. Further research by the same group showed that (R)-citalopram also enhances binding of escitalopram, 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. 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. In a preclinical study in rats combining escitalopram with a P-glycoprotein inhibitor enhanced its antidepressant-like effects.

History

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. 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" (also called "lifecycle management")– 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. 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.

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

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.

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 by what he witnessed at Forest.

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. 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."

In Britain, the form Cipralex costs £14.91, while Lundbeck's older Cipramil can be found for £1.31. The Independent newspaper reported that this costs Britain's National Health Service (NHS) almost £25m extra per year, with no clear clinical benefits. The Independent also describes the patenting of escitalopram as an example of evergreening — slightly changing a drug that is about to go off-patent in order to acquire a patent for the new version, despite its containing similar ingredients to the previous version. Lundbeck has denied that it has "evergreened" escitalopram.

Brand names

Escitalopram is sold under the following brand names:

• Animaxen — Colombia
• Anxipram (GenPharma) — India
• Anxiset-E — India
• Cipralex (Lundbeck)
• Citalin
• Citram — Croatia
• Ecytara (KRKA) — Slovenia
• Elicea (KRKA) — Russia
• Entact — Greece
• Escital — Nigeria
• Escitalopram Actavis (Actavis) — Finland

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• Escitil (Egis) — Czech Republic
• Esertia — Spain
• Esitalo — Australia
• Esopram Actavis (Actavis) — Iceland
• Esto (Unipharm Ltd.) — Israel
• Escitalopram Teva (Teva) — Israel
• Exodus — Brazil
• Ezopram (Actavis) — Ukraine
• Feliz-s - india
• Fubianil — Pakistan
• Lenuxin (Richter Gedeon) — Czech Republic, Russia
• Lexam

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• Lexamil — South Africa
• Lexapro (Forest Laboratories)
• Losita (Eskayef Bangladesh) — Bangladesh
• Miracitol (Orion Corporation) — Russia
• Nexito (Sun Pharmaceutical)
• Reposil — Chile
• Selectra (Actavis) — Russia
• Selpram — Pakistan
• Seroplex (Lundbeck) — France
• Sipralexa (Lundbeck) — Belgium
• Stalopam (Lupin Limited) — India

References

• "A Drug Maker’s Playbook Reveals a Marketing Strategy" article in The New York Times by Gardiner Harris, September 1, 2009

Cited texts

• Royal Pharmaceutical Society of Great Britain (2009). British National Formulary (BNF 58). UK: BMJ Group and RPS Publishing. ISBN 978-0-85369-778-7. {{cite book}}: Unknown parameter |month= ignored (help)

External links

• U.S. National Library of Medicine: Drug Information Portal — Escitalopram
• Lexapro (Forest Laboratories) Official Lexapro homepage
• Cipralex (Lundbeck) Official Cipralex homepage
• Pharmacological information Lexapro
• Cipla Medpro Official Cipla Medpro homepage