escitalopram - world health organization
TRANSCRIPT
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Application for Inclusion to the 21st Expert Committee on the
Selection and Use of Essential Medicines:
ESCITALOPRAM
December 7, 2018
Submitted by:
Iona K. Machado, M.D., Csilla Lippert, M.D.,Ph.D.., Ricardo Lozano, M.D., Michael J.
Ostacher, M.D., MPH, MMSc
Primary Contact: Iona K. Machado, M.D., +1-650-721-4421, [email protected]
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TABLE OF CONTENTS
Page 3 1. Summary Statement
Page 4 2. Focal Point Person in WHO
Page 5 3. Name of the Submitting Organization
Page 6 4. International Proprietary Name
Page 7 5. Formulation Proposed for Inclusion & Current Availability
Page 10 6. Listing Requested
Page 11 7. Treatment Details
Page 16 8. Public Health Relevance
Page 19 9. Comparative Efficacy
Page 23 10. Comparative Safety
Page 43 11. Comparative Cost-Effectiveness
Page 50 12. Regulatory Status
Page 51 13. Pharmacoepial Standards
Page 52 14. References
Page 61 APPENDIX: Letters of Support
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1. Summary statement of the proposal for inclusion of escitalopram
This is a proposal to include escitalopram on the core WHO Model List of Essential Medications
(EML) to treat adults age 18+ with major depressive disorder. The latest EML includes a
member of the tricyclic antidepressant (TCA) class, amitriptyline, and one member of the
selective serotonin reuptake inhibitor (SSRI) class, fluoxetine. We provide a review of evidence
on efficacy, safety, availability, and cost-effectiveness of escitalopram, another member of the
SSRI class, for the treatment of depression in adults.
Escitalopram was first introduced to market in 2002 in the United States and has become a
generically available product as of 2012. It approved for the treatment of major depression, as
well as generalized anxiety disorder, in several countries and is a frequently prescribed
medication globally for these indications. Since it has become generic, its cost has dropped
significantly, increasing its availability globally as well as its cost-efficacy.
The antidepressant class of SSRIs is recommended as first-line treatment for depression per
several international guidelines. Research exploring differences in efficacy and tolerability
between the members of the SSRI class has expanded significantly in the last several years. A
major, GRADE-reviewed, network meta-analysis of over 500 double-blinded randomized
controlled trials published up until 2016, found small but significant advantages to escitalopram
over other SSRIs and other antidepressants on both efficacy and tolerability measures. Based on
these results, escitalopram is one of the best, if not the best, generically available antidepressant.
Escitalopram may confer a particular advantage over the currently listed antidepressants on the
EML because of an improved side-effect profile as compared to amitriptyline and no potent
effect on hepatic cytochrome enzymes, in contrast to fluoxetine. These features of escitalopram
may be particularly useful in the treatment of the elderly, who may not be able to tolerate the
side effects of amitriptyline long enough to stay on the medication and who may be on other
medications whose metabolism is altered by fluoxetine. Given that peak prevalence of
depression is in older persons above age 55, it is particularly important to include safe, tolerable
medications for the treatment of depression to target this population.
Cost-effectiveness analyses, with and without pharmaceutical funding, have largely found
escitalopram to be equal or better than comparator drugs. As the majority of these studies were
completed while escitalopram was under patent, it is likely that the cost-effectiveness profile of
escitalopram has only improved since 2012.
This proposal therefore argues for inclusion of escitalopram as an efficacious, tolerable, and
cost-effective medication for the treatment of depression.
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2. Relevant WHO technical department and focal point
Dr. Tarun Dua, MD, MPH
Programme Manager
Department of Mental Health and Substance Abuse
WORLD HEALTH ORGANIZATION
E-mail: [email protected]
Phone: 41 22 7913059
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3. Name of organization consulting/supporting the application
Stanford University
6
4. International Nonproprietary Name (INN, generic name) of the medicine
INN: escitalopram
ATC: N06AB10
7
5. Formulations of escitalopram proposed for inclusion
Core List
Tablet 10 mg
Current Market Availability:
Antidex (CR, DO, GT, HN, NI, PA, SV); Asitaloks (UA); Celtium (EC); Cilentra (LK); Cipralex
(AE, AT, BG, BH, CH, CY, CZ, DE, DK, EE, EG, ES, FI, GB, GR, HR, HU, IE, IL, IN, IQ, IR,
IS, IT, JO, KW, LB, LT, LY, MT, NO, OM, PK, PL, PT, QA, RO, RU, SA, SE, SI, SK, SY, TR,
YE); Citalam (BD); Citalo (KR); Citao (TW); Citaplex (KR); Clomentin (TR); Conjupram (PH);
Depram (ID); Depresan (UA); Depsit (LK); E-Zentius (PE); Ecinil (LK); Edpa (KR); Elapram
(ID); Elxion (ID); Epram (BD, TW, UY); Esciprex (IE); Escital (KR); Escitalpro (IE); Escivex
(PH); Esidep (TH); Esipram (AU); Esitalo (AU, HK, PH); Eslopran (CO); Esopam (TH);
Esoplex (LB); Esram (HR); Estimex (PY); Esto (IL); Estoram (KR); Etalopro (IE); Feliz S (PH);
Feliz S 10 (ZW); Feliz S 20 (ZW); Feliz-20 (TZ); Ipran (CL, CO); Jovia (PH); L-Xapam (KR);
Leeyo (TW); Lenuksyn (UA); Lepax (TW); Lexacure (KR); Lexam (AU); Lexapam (KR);
Lexapro (AR, AU, BB, BM, BR, BS, BZ, CN, EC, GY, HK, IE, JM, JP, KR, MY, NL, NZ, PE,
PH, PR, SG, SR, TH, TT, TW, VE); Lexapro Meltz (KR); Lexatin (KR); Lexcitam (KR); Lexdin
(PH); Loxalate (AU); Neolexa (LK); Neopra (HK); Newpram (KR); Nexito (PH); Nodep (LK);
Oxapro (LK); Pramokline (MY); Recita (IN); S-Celepra (PH); S-Oropram (HK, MT); Saropram
(KR); Seropam (BD); Seroplex (FR); Sipralexa (BE); Spador (BD); Talopram (PY); Zelax (LB,
QA); Zytapram (PH)
Lexi-comp
1. Aciprex (DI) (Form Not
Given) Biofarm, Pol. Poland 8298136
ESCITALOPRAM -
DRUGDEX
2. Aloce (FM) (Form Not
Given) Miklich, Port. Spain 8411708
ESCITALOPRAM -
DRUGDEX
3. Alvoplex
(FM)
(Form Not
Given) Alvogen, Cz.
Czech
Republic 8153345
ESCITALOPRAM -
DRUGDEX
4. Anxila (Form Not
Given) KRKA, Cz.
Czech
Republic 8289110
ESCITALOPRAM -
DRUGDEX
5. ApoEscitaxin (Form Not
Given) Apotex, Pol. Poland 8339344
ESCITALOPRAM -
DRUGDEX
6. Benel (Form Not
Given)
Farmalider,
Denm. Spain 8325098
ESCITALOPRAM -
DRUGDEX
7. Betesda (Form Not
Given) Axxon, Pol. Poland 8257956
ESCITALOPRAM -
DRUGDEX
8. Bositalex (Form Not
Given) Chanelle, Cz. Ireland 8373440
ESCITALOPRAM -
DRUGDEX
9. Calolex (FM) (Form Not
Given) Chanelle, Port. Ireland 8343924
ESCITALOPRAM -
DRUGDEX
10. Calolex (Form Not
Given) Chanelle, Denm. Ireland 8382392
ESCITALOPRAM -
DRUGDEX
11. Celtium (Form Not Saval, Chile Chile 8176843 ESCITALOPRAM -
8
Given) DRUGDEX
12. Cesopil (FM) (Form Not
Given) Chanelle, Cz. Ireland 8343607
ESCITALOPRAM -
DRUGDEX
13. Cilopam-S (Form Not
Given) Eris, Austral. Australia 8315871
ESCITALOPRAM -
DRUGDEX
14. Cipralex
(FM)
(Form Not
Given) Lundbeck, Indon. Indonesia 8171373
ESCITALOPRAM -
DRUGDEX
15. Cipralex
(FM)
(Form Not
Given) Lundbeck, Neth. Netherlands 8361353
ESCITALOPRAM -
DRUGDEX
16. Cipralex (Form Not
Given)
Lundbeck,
Austria Austria 8246468
ESCITALOPRAM -
DRUGDEX
17. Cipralex (Form Not
Given) Lundbeck, Canad. Canada 8381059
ESCITALOPRAM -
DRUGDEX
18. Cipralex (Form Not
Given) Lundbeck, Cz.
Czech
Republic 8332969
19. Cipralex (Form Not
Given) Lundbeck, Denm. Denmark 8341866
ESCITALOPRAM -
DRUGDEX
20. Cipralex (Form Not
Given) Lundbeck, Fin. Finland 8218595
ESCITALOPRAM -
DRUGDEX
21. Cipralex (Form Not
Given) Lundbeck, Ger. Germany 8328732
ESCITALOPRAM -
DRUGDEX
22. Cipralex (Form Not
Given) Lundbeck, Gr. Greece 8405009
ESCITALOPRAM -
DRUGDEX
23. Cipralex (Form Not
Given) Lundbeck, Hung. Hungary 8174861
24. Cipralex (Form Not
Given) Lundbeck, Israel Israel 8236059
ESCITALOPRAM -
DRUGDEX
25. Cipralex (Form Not
Given) Lundbeck, Ital. Italy 8406384
ESCITALOPRAM -
DRUGDEX
26. Cipralex (Form Not
Given) Lundbeck, Norw. Norway 8233342
ESCITALOPRAM -
DRUGDEX
27. Cipralex (Form Not
Given) Lundbeck, Port. Portugal 8225781
ESCITALOPRAM -
DRUGDEX
28. Cipralex (Form Not
Given) Lundbeck, S.Afr. South Africa 8329443
ESCITALOPRAM -
DRUGDEX
29. Cipralex (Form Not
Given) Lundbeck, Spain Spain 8415507
ESCITALOPRAM -
DRUGDEX
30. Cipralex (Form Not
Given) Lundbeck, Swed. Sweden 8369097
ESCITALOPRAM -
DRUGDEX
31. Cipralex (Form Not
Given) Lundbeck, Switz. Switzerland 8427809
ESCITALOPRAM -
DRUGDEX
32. Cipralex (Form Not
Given) Lundbeck, Turk. Turkey 8213051
ESCITALOPRAM -
DRUGDEX
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33. Cipralex (Form Not
Given) Lundbeck, UK
United
Kingdom 8240472
ESCITALOPRAM -
DRUGDEX
34. Cipralex (Form Not
Given) Lundbeck, Ukr. Ukraine 8407415
ESCITALOPRAM -
DRUGDEX
35. Citoles (Form Not
Given) Abdi, Turk. Turkey 8314803
ESCITALOPRAM -
DRUGDEX
36. Citraplax (Form Not
Given) Chanelle, Neth. Ireland 8291940
ESCITALOPRAM -
DRUGDEX
37. Codepric (Form Not
Given) Pentafarma, Port. Portugal 8318928
ESCITALOPRAM -
DRUGDEX
38. Conjupram (Form Not
Given) Akums, Philipp. Philippines 8439887
ESCITALOPRAM -
DRUGDEX
39. Depart (FM) (Form Not
Given) Atral, Port. Portugal 8337668
ESCITALOPRAM -
DRUGDEX
40. Depralin (Form Not
Given) Polpharma, Pol. Poland 8362850
ESCITALOPRAM -
DRUGDEX
41. Depram (Form Not
Given) Novell, Indon. Indonesia 8437065
ESCITALOPRAM -
DRUGDEX
42. Depresinal (Form Not
Given) GL Pharma, Cz. Austria 8330562
ESCITALOPRAM -
DRUGDEX
43. Deprigen (Form Not
Given) Biogened, Pol. Poland 8363423
ESCITALOPRAM -
DRUGDEX
44. Deprilept (DI) (Form Not
Given) Ranbaxy, Pol. Poland 8352335
ESCITALOPRAM -
DRUGDEX
45. Despra (FM) (Form Not
Given) Glenmark, Cz.
Czech
Republic 8182751
ESCITALOPRAM -
DRUGDEX
46. Dexan (DI) (Form Not
Given)
Julius Chen,
Hong Kong Hong Kong 8434150
ESCITALOPRAM -
DRUGDEX
47. Diprex (Form Not
Given) Vir, Spain Spain 8211745
ESCITALOPRAM -
DRUGDEX
48. Eciprax (FM) (Form Not
Given) Labomed, Chile Chile 8194455
ESCITALOPRAM -
DRUGDEX
49. Ecitalex (Form Not
Given) Andromaco, Chile Chile 8305094
ESCITALOPRAM -
DRUGDEX
50. Ecitrix (FM) (Form Not
Given) Ratiopharm, Port. Portugal 8186176
ESCITALOPRAM -
DRUGDEX
Source: Micromedex
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6. Listing requested as
Individual medicine
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7. Treatment details for escitalopram
7.1 Dosing and Duration
Escitalopram dosage forms (1):
Tablet: 5 mg, 10 mg (scored), 20 mg (scored)
Capsule: 5 mg, 10 mg, 20 mg
Oral Solution: 5 mg/5 mL
Usual dosage range (1):
10-20 mg/day
Onset of action (1):
2-4 weeks, if not working within 6-8 weeks it may require a dosage increase or it may not work
at all.
Long-term use (1):
May continue for many years to prevent relapse of symptoms. It is indicated for the acute and
maintenance treatment of major depressive disorder in adults and adolescents 12 to 17 years of
age.
Dosage guidelines for oral formulation approved uses for escitalopram (1,2):
Escitalopram has US Food and Drug Administration (FDA)-approved uses for major depressive
disorder in adults (ages 18 and older) and adolescents (between ages 12-17) and generalized
anxiety disorder in adults.
Unless otherwise noted escitalopram may be administered on a once daily schedule morning or
evening.
Initial
Dose
Titration Target Dose Effective Dose
Major Depressive
Disorder (adolescents)
10 mg/day 10 mg in 3
weeks
20 mg daily 20 mg daily
Major Depressive
Disorder (adults)
10 mg/day 10 mg in 1 week 20 mg daily 20 mg daily
Generalized Anxiety
Disorder (adult)
10 mg/day 10 mg in 1 week 20 mg daily 20 mg daily
7.2 Special Populations (1,2)
Elderly:
10 mg/day is the recommended dose for most elderly patients and patients with hepatic
impairment. Risk of SIADH with SSRIs is higher in elderly.
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Children and adolescents:
Approved for depression in adolescents aged 12-17. Use with caution, observing for activation of
known, or unknown, bipolar disorder and/or suicidal ideation, and inform parents or guardians of
the risk so they can help observe the child or adolescent. Decreased appetite and weight loss
have been observed with use of SSRIs. Consequently, regular monitoring of weight and growth
should be performed in children and adolescents treated with escitalopram.
Renal impairment:
No dose adjustment is necessary for patients with mild or moderate renal impairment.
Escitalopram should be used in caution in patients with severe renal impairment.
Hepatic impairment:
Recommended dose 10 mg/day
Pregnancy:
As controlled studies are few in pregnant women, escitalopram is not generally recommended for
use during pregnancy, especially during first trimester. However, continuous treatment during
pregnancy may be necessary and has not been proven to be harmful to the fetus. Exposure to
SSRIs early in pregnancy may be associated with risk of septal heart defects (absolute risk
small). Neonates exposed to SSRIs or SNRIs late in third trimester have developed
complications requiring prolonged hospitalization, respiratory support, and tube feeding;
reported symptoms are consistent with either a direct toxic effect of SSRIs and SNRIs or,
possibly, a drug discontinuation syndrome, and include: respiratory distress, cyanosis, apnea,
seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia,
hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.
Breast feeding:
Some drug is found in mother’s breast milk. If child becomes irritable or sedated, breast feeding,
or drug, may need to be discontinued.
7.3 Pharmacokinetics (1,2)
Metabolized by CYP3A4 and -2C19. Escitalopram is metabolized by multiple enzyme systems,
inhibition of single enzyme may not appreciably decrease escitalopram clearance.
No significant action on CYP450 enzymes.
- Mean terminal half-life: 27-32 hours
- Time to steady-state in plasma concentration with once-daily dosing: 1 week
- The tablet and oral solution dosage forms are bioequivalent
- Time to peak blood levels: 5 hours
- Absorption not affected by food
7.4 Other Considerations
Overdose (2):
Overdose with escitalopram has been rarely reported. Symptoms of overdose, alone or in
combination with other drugs and/or alcohol, include convulsions, coma, dizziness, hypotension,
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insomnia, nausea, vomiting, sinus tachycardia, somnolence, and ECG changes (including QT
prolongation and very rare cases of torsade de pointes). Acute renal failure has been very rarely
reported accompanying overdose.
In management of overdose establish and maintain an airway to ensure adequate ventilation and
oxygenation. Consider gastric evaluation by lavage and activated charcoal. Monitor cardiac and
vital signs, along with general supportive care. There are no specific antidotes for Lexapro.
Dependence or abuse (1):
None known.
Discontinuation (1,2):
Taper not usually necessary, but it may be helpful to taper in order to avoid potential withdrawal
reactions. Many people tolerate 50% dose reduction for 3 days then another 50% reduction for 3
days then discontinuation. If adverse reactions including dysphoric mood, irritability, agitation,
dizziness, sensory disturbances (paresthesias such as electric shock sensations), anxiety,
confusion, headache, lethargy, emotional lability, insomnia, and hypomania raise the dose to stop
symptoms and then restart withdrawal much more slowly.
Storage and handling (2):
Store escitalopram at 25C (77F); excursions permitted to 15 – 30C (59 – 86F)
Keep escitalopram bottle closed tightly
7.4 Guideline Recommendations
The WHO guidelines for the treatment of depression does not distinguish between different
members of the SSRI class, though recommends that tricyclic antidepressants or fluoxetine
should be considered in adults with a moderate to severe depressive episode/disorder (3). These
treatments should also be considered in women suffering from a depressive episode who are
planning a pregnancy, pregnant or breastfeeding, if drug treatment is required. The WHO
guidelines recommend avoiding use of TCAs in the elderly. The strength of these
recommendations is rated as “standard.”
Given no specific recommendations on utilization of different members of the SSRI class,
guidelines from different countries were consulted and are summarized below.
The National Institute for Health and Care Excellence (NICE) guidelines from the United
Kingdom (UK) list several benefits to the class of SSRIs, as it is associated with fewer
anticholinergic side effects, less likely to cause postural hypotension or sedation, less necessity
for dosage titration which implies that subtherapeutic doses are less likely to be prescribed, less
cardiotoxic, and much safer in overdose than the TCAs or MAOIs. The guidelines specify that
fluvoxamine, fluoxetine and paroxetine are inhibitors of various hepatic cytochrome
metabolizing enzymes which therefore precipitate several significant drug-drug interactions.
NICE identifies sertraline as less problematic (though enzyme inhibition is dose-related) in this
regard and citalopram and escitalopram as relatively safe. In accordance, the NICE guidelines
recommend a generic SSRI as the first choice given its favorable risk-benefit ratio. It specifically
14
cautions that SSRIs may increase risk of bleeding and to be particularly cautious in the elderly
who are concurrently taking an NSAID or aspirin. In terms of recommendations relevant to the
current antidepressants listed on WHO’s EML, amitriptyline and fluoxetine, the guidelines urge
clinicians to consider that venlafaxine, duloxetine, and TCAs confer an increased likelihood of
patient discontinuation due to side effects and that TCAs specifically confer a risk of orthostatic
hypotension and arrhythmias (4).
Compared to the 2010 guideline, the 2018 guideline included a new section on escitalopram
specifically, as several studies have been published about its efficacy since 2010. The NICE
guidelines summarize escitalopram as superior to placebo in the treatment of depression, with
some evidence suggestive of more efficacy at 20 mg compared to 10 mg, but at the cost of more
side effects. It designated escitalopram as more effective than citalopram (small effect size) and
at least as effective as other SSRIs, if not perhaps more effective (statistically significant
differences, but of small effect size of unlikely clinical importance). with marginally better
tolerability, except as compared to sertraline. Overall, the NICE guidelines concluded that choice
of antidepressant should largely be guided by side-effect profile, patient preference, and previous
treatment experience (4).
The Canadian Network for Mood and Anxiety Treatments (CANMAT) guideline for the
treatment of depression, published in 2016, names escitalopram as a “first line” treatment, along
with all other SSRIs, including fluoxetine. Amitriptyline is listed as “second line” treatment. The
guidelines specifically summarize the results of its literature search as “some antidepressants
have modest superiority for treatment response, particularly escitalopram, mirtazapine, sertraline,
and venlafaxine.” Escitalopram is listed as a drug that confers “minimal or low potential” for
drug-drug interactions, in contrast to fluoxetine which confers a “higher potential,” given that it
is a potent CYP2D6 and CYP2C19 inhibitor (5).
The American Psychiatric Association (APA) guidelines, published in 2010, did not find any
evidence to suggest superiority of another antidepressant class or agent over the SSRIs, and
named one meta-analysis suggestive of slight superiority of escitalopram over other SSRIs and
venlafaxine and another suggestive of escitalopram, sertraline, venlafaxine, and mirtazapine as
superior to duloxetine, fluoxetine, fluvoxamine, and paroxetine. These guidelines do not reflect
the greater body of evidence comparing different antidepressants that have been published since
2010. The guidelines recommend starting at 10 mg/day with a maximum dose of 20 mg/day. The
APA guidelines also support escitalopram’s favorable drug-drug interaction profile over that of
fluoxetine, fluvoxamine, and paroxetine (6).
Royal Australian and New Zealand College of Psychiatrists (RANZP) recommends SSRIs,
including escitalopram, as first-line treatment due to its reasonable efficacy and tolerability
profile. TCAs are designated as second-line treatment due to tolerability and safety concerns (7).
The South African Society of Psychiatrists guidelines also recommend SSRIs, including
escitalopram, or SNRIs as first-line treatment (8).
The American Geriatrics Society has developed a list of medications to avoid in the elderly due
to various side effects, known as the Beers’ Criteria (9). Amitriptyline as well as several other
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members of the tricyclic antidepressant class (clomipramine, desipramine, imipramine,
nortriptyline, for example) and one SSRI (paroxetine), are strongly recommended with high
quality evidence to avoid use in the elderly due to its “highly anticholinergic, sedating, and cause
orthostatic hypotension” properties. SSRIs (along with TCAs, SNRIs, and mirtazapine) are
strongly recommended with moderate evidence to “use with caution” in the elderly due as these
medications may cause or exacerbate syndrome of inappropriate anti-diuretic hormone secretion.
The Beers Criteria also strongly recommends, with high quality evidence, to “avoid” SSRIs in
patients with a history of fractures or falls as they may cause or exacerbate ataxia, impaired
psychomotor function, syncope, or additional falls. SSRIs and TCAs should be avoided (strong
recommendation, moderate quality evidence) if the patient is already on ≥2 CNS-active drugs to
minimize increased risk of falling (9). A similar Italian guideline lists amitriptyline as a drug that
should be “always avoided,” due to its side effect profile as mentioned above, and fluoxetine as
“rarely appropriate” for the elderly ≥ 65 years old, citing its long half‐ life and presence of active
metabolites as problematic (10). The guideline recommends consideration of fluoxetine when
other agents have failed.
In summary, several international guidelines recommend SSRIs as a first-line treatment for
depression (4–8) and some guidelines note possible superiority of escitalopram over other SSRIs
with respect to efficacy and tolerability (4–6). With respect to the elderly, SSRIs are considered
first-line pharmacotherapy, with strong recommendations against use of TCAs (9,10).
Fluoxetine, the other antidepressant on the WHO EML, confers limitations due to its CYP
enzyme inhibition (4–6,9,10), that may limit its use in patients on multiple other medications,
such as the elderly.
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8. Information supporting the public health relevance
8.1 Disease Burden Depression is estimated to affect 322 million people as of 2015, approximately 4.4% of the
global population. It has a peak prevalence both in men (5.5%) and women (7.5%) in later
adulthood (ages 55-74). Depression was responsible for over 50 million years lived with
disability (YLDs) globally in 2015 and, at 7.5% of all YLDs, is the largest single contributor to
non-fatal health loss (11). Over 80% of this burden is shouldered by low- and middle-income
countries. To use a related metric, another study using data from the Global Burden of Diseases,
Injuries, and Risk Factors Study 2010 estimated that depression accounted for approximately
74.4 million disability-adjusted life years (DALYs) worldwide, representing 40.5% of DALYs
caused by mental and substance use disorders and 3.0% of all DALYs worldwide (12).
The class of antidepressants known as the selective serotonin reuptake inhibitors (SSRIs) are
broadly recommended as the first-line treatment for depression (4–8). Escitalopram is the latest
drug to be added to the class of SSRIs and recently lost patent in 2012. Whereas citalopram is a
racemic mixture of the active ingredient, escitalopram contains only the s-enantiomer of
citalopram, 100 times more potent and with theoretically fewer side effects than r-citalopram (4).
Given that approximately 20-30% of patients do not respond adequately to their first
antidepressant (assuming appropriate dosage, treatment time, and medication adherence) and that
about 50% of this population respond to their second (4), there should be a safe, efficacious,
antidepressant available as an alternative. The U.S. guidelines draw no distinction between
switching to an agent of the same class or to an agent of a different class (6), nor does the U.K.
guidelines, though the latter suggests a small efficacy advantage to switching to venlafaxine or
escitalopram of dubious clinical significance (4). Given numerous considerations in the
prescription of amitriptyline that may limit its clinical use, escitalopram, for its efficacy,
tolerability, minimal potential for drug-drug interactions, is not only useful as a first-line
treatment in several populations, but also as a switch option for those who do not demonstrate
sufficient improvement on fluoxetine.
8.2 Assessment of Current Use Escitalopram was the fourth most frequently prescribed antidepressant in the United States at
25.2 million prescriptions in 2016, and the 26th
most prescribed drug overall. Comparatively,
trazodone ranked #24 overall with 25.3 million prescriptions, citalopram #21 overall with 26.4
million prescriptions, and sertraline #14 overall with 37.1 million prescriptions. The indication
for these medications, however, was not specified, and could encompass treatment for insomnia
(particularly likely for trazodone) (13). The Centers for Disease Control and Prevention (CDC)
in the United States analyzed Truven Health’s 2008–2013 MarketScan Commercial Claims and
Encounters databases, a large convenience sample of clients with private employer-sponsored
insurance, to assess outpatient prescription antidepressant claims for women aged 15-44 years
(reproductively aged), approximately 5.8 million women per year. From 2008-2013, the most
common antidepressant prescriptions were sertraline (an average of 3.3% over this time period),
bupropion (2.7%), citalopram (2.6%), escitalopram (2.5%), and fluoxetine (2.3%) (14).
17
A study of Australia’s Drug Utilisation Sub-Committee, which contains outpatient prescription
data of both subsidized and non-subsidized drugs including prescriptions from private clinics,
reported antidepressant use over a 12-year period (2000-2011) as defined daily dose (DDD) per
1000 persons of the population per day (15). Sertraline was the highest dispensed in 2011 at
21.4% of total DDDs/1000/day, followed by escitalopram at 14.7% and venlafaxine at 13.9%.
Fluoxetine represented 7.1%.
In a study of 706 patients aged 16-65 who met criteria for depression, recruited from 16 centers
across India (with diversity in facility-type, from teaching institutions to privately run psychiatric
clinics), escitalopram was the most commonly prescribed antidepressant at 40% of all
antidepressant prescriptions, followed by sertraline at 17% and fluoxetine at 16% (16). A larger
cross-sectional study published by the same group in 2014, consisting of 4480 patients aged 16-
65 using psychiatric services across 11 centers, found similar results; 33.8% of the sample
received prescriptions for escitalopram, making it the most frequently prescribed antidepressant
as compared to sertraline 19%, amitriptyline 11.5%, and fluoxetine 9.3% (17). An analysis of the
Hospital Purchase of Drug Information System from 32 hospitals in different administrative
districts of China’s Wuhan province, representing both urban and rural hospitals, found that as of
2012, escitalopram had the second highest utilization (0.589) to paroxetine (0.639), measured as
defined daily doses per 1000 inhabitants per day (18). In 2013, across 40 psychiatric centers in
10 Asian countries (China, Japan, Korea, Singapore, Taiwan, India, Indonesia, Malaysia, and
Thailand) included in the Research on Asia Psychotropic Prescription (REAP) project, who were
prescribed an antidepressant in a three-month window in 2013 (19). Fluoxetine (16%), sertraline
(15%), and escitalopram (14%) were the top 3 prescribed antidepressants.
In a prospective, descriptive cohort study of “nationally representative medicine claims data
submitted to a privately owned South African pharmaceutical benefit management (PBM)
company,” representing all antidepressant prescriptions for 407,586 patients over a 6-year study
period from 2006-2011, escitalopram was the second most prescribed antidepressant at 14.6% of
all antidepressant prescriptions, with venlafaxine at 14.9% topping the list. By contrast,
fluoxetine and amitriptyline made up 6.0% of the prescriptions each (20).
A study of France’s main national health insurance (representing 75% of the French population),
SNIIRAM (Système National d'Information Inter‐ Régimes de l'Assurance Maladie) database
records, specifically isolating new antidepressant prescriptions (the client must not have had any
psychiatric diagnoses in the past 4-5 years and no prior prescription of psychotropics in 2009 and
2010) in 2011, found that of the 998,710 adults initiating an antidepressant, escitalopram was
prescribed the most frequently (33%), followed by paroxetine (15%), amitriptyline (11%),
fluoxetine (7%) and venlafaxine (7%) (21). In a Danish study evaluating prescribing patterns in
2009-2010, escitalopram was more commonly chosen as the first SSRI over citalopram and
sertraline (n = 65,313 prescriptions for treatment-naïve patients, 19% of which were for
escitalopram with higher rates when psychiatrists and hospital physicians were the prescribers)
(22).
8.3 Target Population Escitalopram has been most studied in adult populations, ages 18 and up. The efficacy of
escitalopram in the adult population is detailed below, but escitalopram offers a distinct
18
advantage over the currently listed WHO EML antidepressants, amitriptyline and fluoxetine,
particularly for the elderly. Escitalopram is metabolized by three CYP450 isozymes in parallel
and is neither an inducer nor a significant inhibitor of CYP450. Moreover, since its protein-
binding is low, escitalopram presents a low risk of clinically relevant drug–drug interactions
(23). Several national guidelines cite escitalopram’s pharmacological profile as advantageous
over fluoxetine (see section 7 for more details) and its adverse event profile as advantageous
over TCAs, like amitriptyline, which are recommended by a number of national treatment
guidelines as second-line treatment for the treatment of depression (4–6).
8.4 Likely Impact of Treatment on the Disease Antidepressants take several weeks to take effect (4–7) but a patient's tolerance of the medication
may not be sufficient. There is evidence to suggest improved tolerability over currently listed
WHO EML antidepressants (24), thereby increasing the likelihood that patients stay on the
medication long enough and that escitalopram may be safer in populations for whom fluoxetine
or amitriptyline is not an ideal choice – for example, in patients on drugs whose metabolism may
be affected by fluoxetine (4–6), or patients with heart conditions such as cardiac instability or
ischemia for whom the risk of arrhythmia with amitriptyline is too great (4,6), or elderly patients
for whom amitriptyline is strongly recommended to avoid to prevent morbidity related to its side
effects (9,10). Given the estimate that the peak prevalence in both men and women is in older
adulthood (ages 55-74), there is likely a worldwide population that remains un- or undertreated, a
group in which fluoxetine and amitriptyline may be relatively contraindicated, calling for a need
to include a more tolerable and efficacious medicine, one that the population may adhere to drug
treatment long enough to appreciate benefit.
19
9. Comparative efficacy, review of benefits
Given that the strongest evidence for the comparative efficacy and tolerability of 21
antidepressants is derived from one network meta-analysis, this section will first review and
summarize that publication and will then review other publications.
9.1 Network Meta-Analysis
The comparative efficacy and tolerability of antidepressants was comprehensively studied by one
network meta-analysis published in February 2018 (24), a more expansive update to the same
group’s original network meta-analysis published in 2009 (25). As it is the largest and most
robust dataset and analysis on the topic, results from this paper form the principal argument for
the inclusion of escitalopram to the essential medicines list and are summarized as follows.
The latest network meta-analysis of 522 double blinded, randomized controlled trials published
from 1979 to Jan 8, 2016, comprising 116,477 participants, compared the following
antidepressants to each other or to placebo for the treatment of unipolar depression: agomelatine,
bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine,
levomilnacipran, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, venlafaxine,
vilazodone, vortioxetine, amitriptyline, clomipramine, trazodone, and nefazodone (24). The
acute treatment phase was set at 8 weeks, but data from a 4-12 week treatment time period was
used if the 8-week point was not available. The primary outcomes were defined as 1) efficacy -
50% reduction from baseline score on a standardized observer-rating scale for depression (for
example, the Hamilton depression rating scale (HDRS) or Montgomery-Asberg depression rating
scale (MADRS)), and 2) acceptability – all-cause discontinuation, which encompasses both
efficacy and tolerability. Secondary outcomes were set as: final depression rating scale score,
remission rate, drop-out rate due to adverse events.
20
Of the included 522 trials, the majority were
from North America (48%, n=252) and
Europe (11%, n=59). However, 37 trials (7%)
recruited patients from Asia, 59 (11%) from
cross-continental areas, and 34 (7%) from
other or unspecified regions. The vast majority
of patients, from 464 (89%) trials, had
moderate-to-severe major depressive disorder,
quantified as a mean reported baseline HDRS
17-item score of 25.7. It is worthwhile noting
that the majority, 409 (78%) trials, were
funded by pharmaceutical companies. Forty-
two trials compared escitalopram to placebo
or another comparator.
As per the initial study protocol, the primary
analysis was derived from the 474 studies
(encompassing 106,966 participants) that
compared medications at dosages within the
licensed range approved by US and/or
European regulatory agencies. Figure 1 is a
summary analysis of 432 RCTs (total
n=102,443) for the efficacy figure and 422
RCTs (total n=99,787) for the acceptability
figure. Escitalopram carries a modest effect
size, odds ratio of 1.68 with a relatively
narrow 95% credible interval (CrI) of 1.50,
1.87, while conferring a non-significantly
improved drop-out rate compared to placebo
(OR 0.90, 95% CrI (0.80, 1.02). Secondary
outcome data for remission (OR 1.64, 95%
CrI (1.47, 1.83)) and drop-out rate (OR 1.72,
95% CrI (1.38, 2.14), in the supplementary
material, are shown in Figure 2.
The authors estimated the median
heterogeneity variance for efficacy at 0.044
(95% CrI 0.028–0.063) and 0.040 (0.023–
0.062) for acceptability, suggesting moderate-
to-low heterogeneity on both accounts. Per
subgroup meta-regression analyses, the
strongest explanation for this was the
inclusion of placebo. When placebo-controlled
trials were excluded, heterogeneity variance
was reduced by 24% for response and 45% for
dropout. Other subgroup analyses revealed Figure 1. Forest plots of network meta-analysis of all trials for efficacy (A) and acceptability (B)
21
that smaller and older studies were more likely to find larger effect sizes for the active drug
against placebo, particularly in trials involving amitriptyline, bupropion, fluoxetine, and
reboxetine. The authors determined risk of bias as high in 46 (9%) of 522 trials, moderate in 380
(73%) trials, and low in 96 (18%) trials.
Figure 3 presents data for efficacy and acceptability derived from 194 head-to-head trials of
licensed doses of two or more active compounds. The figure incorporates GRADE evidence,
with moderate levels of certainty for most of the comparisons involving escitalopram,
agomelatine, citalopram, and mirtazapine. Trials involving vortioxetine, amitriptyline,
clomipramine, bupropion, and nefazodone had low to very low levels of certainty.
Significant findings are bolded and underlined. For the efficacy data, the agent identified by the
column is superior if the odds ratio is greater than 1. If the odds ratio is less than 1 in the
acceptability data, the first drug in alphabetical order is favored. Escitalopram thereby has
moderate level GRADE evidence of superiority in terms of efficacy over citalopram,
clomipramine, fluoxetine, fluvoxamine, reboxetine, and trazodone, making it the agent with
statistically significant superiority over the most other alternative agent amongst these 21 drugs.
In comparison to members of its class, SSRIs, on measures of efficacy, escitalopram appears to
be non-statistically significantly superior to paroxetine (OR 1.12, 95% 0.93-1.35) and sertraline
(OR 1.20, 95% CI 0.97-1.48). With respect to acceptability, escitalopram demonstrates moderate
level GRADE evidence of superiority to duloxetine, clomipramine, amitriptyline, fluvoxamine,
reboxetine, and venlafaxine. No drug was found to be more statistically significantly efficacious
or better tolerated than escitalopram.
Figure 2. Forest plots of network meta-analysis of all trials for remission (left) and drop-outs due to side effects (right)
22
The decision to specifically analyze data from double blind, randomized head-to-head controlled
trials, including unpublished data which generally tends to include more reported adverse side
effects, and the incorporation of GRADE evidence, makes the above findings quite robust. As
seen by comparing Figures 1 and 3, when trials comparing active agents to placebo were
included, estimated differences between drugs were smaller. Figure 4 plots these results side by
side for easier visualization. The authors identify several explanations for this, including: 1)
higher placebo response rates associated with the nature of studies (frequent visits, therapeutic
setting, expectation that one may receive an active treatment), 2) spontaneous improvement of
depression symptoms over time which thereby increase placebo response rates, 3) higher dropout
rates in those receiving the active compound thinking they have received the placebo which then
may underestimate treatment effect via last-observation-carried-forward approach for imputing
missing data or simply not enough treatment time to see an effect, 4) bias derived from industry
interests. On this last point, the authors did not find much association between industry funding
and response or drop-out rate, but only a few of the included trials were not funded by industry.
Figure 3. Head-to-head comparisons for efficacy and acceptability of the 21 antidepressants. OR=odds ratio. CrI=credible interval. Agom=agomelatine. Amit=amitriptyline. Bupr=bupropion. Cita=citalopram. Clom=clomipramine. Dulo=duloxetine. Esci=escitalopram. Fluo=fluoxetine. Fluv=fluvoxamine. Miln=milnacipran. Mirt=mirtazapine. Nefa=nefazodone. Paro=paroxetine. Rebo=reboxetine. Sert=sertraline. Traz=trazodone. Venl=venlafaxine. Vort=vortioxetine. *Moderate quality of evidence. †Low quality of evidence. ‡Very low quality of evidence.
23
In conclusion, the above
evidence identifies
escitalopram as an agent that
maximizes efficacy and
acceptability within the SSRI
class and appears to do so in
comparison to a great
number of non-SSRI
treatments as well. In the
context of the greater body of
literature, this review is the
largest and most robust by
means of study design,
accounting for heterogeneity
and bias, to this author’s
knowledge, and therefore
forms the main argument for
the inclusion of escitalopram
to the essential medicines
list.
A summary of the earlier
version of this review (25)
will not be included here as
this review has encompassed
and expanded upon those
results. The remainder of the
evidence presented here
constitutes other Cochrane
reviews, which have
considerable overlap in
included studies, and non-
double-blind randomized
controlled trials, as those
were not included in this
network meta-analysis.
Figure 4.Two-dimensional graphs about efficacy and acceptability in all studies (A) and head-to-head (B) studies only. Data are reported as ORs in comparison with reboxetine, which is the reference drug. Error bars are 95% CrIs. Individual drugs are represented by different coloured nodes. Desvenlafaxine, levomilnacipran, and vilazodone were not included in the head-to-head analysis because these three antidepressants had only placebo-controlled trials. ORs=odds ratios. 1=agomelatine. 2=amitriptyline. 3=bupropion. 4=citalopram. 5=clomipramine. 6=desvenlafaxine. 7=duloxetine. 8=escitalopram. 9=fluoxetine. 10=fluvoxamine. 11=levomilnacipran. 12=milnacipran. 13=mirtazapine. 14=nefazodone. 15=paroxetine. 16=reboxetine. 17=sertraline. 18=trazodone. 19=venlafaxine. 20=vilazodone. 21=vortioxetine. 22=placebo.
24
9.2 Cochrane Reviews
A search of the Cochrane Database for the key word “escitalopram” on 9/24/18 yielded 15
results. Seven were excluded for irrelevance to the treatment of depression.
Escitalopram v. other antidepressants
An analysis of 22 randomized controlled trials (RCTs) conducted prior to July 2008,
encompassing approximately 4000 subjects, were included in a review of escitalopram for the
treatment of depression compared to other antidepressants (26). The primary outcome was the
number of subjects who responded to escitalopram as compared to another medication (including
tricyclics, heterocyclics, other SSRIs, and other new antidepressants such as SNRIs), defined as a
50% reduction in a depression scale (most commonly the HAM-D, but also the MADRS or other
depression scales). The intention-to-treat approach was utilized to calculate responders and
remitters to treatment and the Cochrane risk-of-bias tool was applied to all included studies.
In 6 studies (n=1823) that compared response rates between escitalopram and citalopram, there
was a statistically significant difference in favor of escitalopram (OR 0.67, 95% CI 0.50 to 0.89,
p = 0.006), also found in remission rates (OR 0.57, 95% CI 0.36 to 0.90, p = 0.02). Three studies
(n=783) that directly compared escitalopram and fluoxetine did not find a statistically significant
difference in response or remission rates but did find escitalopram to be more efficacious than
fluoxetine in reduction of depressive symptoms (SMD ‐ 0.17, 95% CI ‐ 0.32 to ‐ 0.03, p = 0.02;
3 studies, 759 participants) from baseline. Two studies (n=784) that compared escitalopram to
paroxetine, as well as two studies (n= 489) comparing escitalopram to sertraline, did not find any
statistically significant differences on all of the above parameters (response rate, remission rate,
mean change in baseline of depressive symptoms).
On efficacy measures comparing escitalopram to bupropion (3 studies, n=842), there were no
statistically significant differences.
Three studies of 1150 participants comparing escitalopram to duloxetine found no statistically
significant differences on measures of efficacy. In a maximum of 2 studies of 495 subjects, no
statistically significant differences were found on efficacy between escitalopram and
venlafaxine. Sensitivity analyses did not significantly change the above results.
In summary, escitalopram was clinically superior to citalopram, clinically superior to fluoxetine
on one secondary outcome, and equivalent to several other antidepressants (paroxetine,
sertraline, bupropion, duloxetine, and venlafaxine).
Other antidepressants v. escitalopram
The newer review comparing citalopram to escitalopram (27) included one additional study (28)
to the above review focusing on escitalopram and concluded similar results. The authors note
that the included studies were all funded by the same manufacturer of both drugs and therefore
may include the possibility of “wish bias.”
A Cochrane review comparing S‐ adenosyl methionine (SAMe) to escitalopram (29) included
just one low-quality study of 129 participants (30), which did not provide strong evidence for
25
any difference in terms of change in depressive symptoms from baseline to end of treatment as a
monotherapy nor in terms of drop-out rates.
A Cochrane review comparing agomelatine to several other antidepressants (31), including
escitalopram, identified two studies (32,33) that were not able to find evidence that agomelatine
was more or less effective than escitalopram in treatment response (RR 1.05, 95% CI 0.95 to
1.16, P value 0.33, I² = 0%; two trials, 462 participants), remission rates (RR 1.13, 95% CI 0.94
to 1.35, P value 0.20, I² = 0%; two trials, 462 participants), total drop-out rates (RR 0.81, 95% CI
0.50 to 1.32, P value 0.76, I² = 0%; two trials, 462 participants), drop-out rates due to inefficacy
(RR 1.34, 95% CI 0.43 to 4.21, P value 0.61, I² = 0%; two trials, 462 participants) or side effects
(RR 0.40, 95% CI 0.15 to 1.06, P value 0.07; two studies, 462 participants).
A study comparing duloxetine against other antidepressants (34) was excluded because it used
the same 3 studies as in the aforementioned review comparing escitalopram to other
antidepressants (26).
Special populations
The Cochrane review assessing risk and benefits of antidepressant use, including escitalopram, in
patients with co-morbid depression and alcohol dependence found that antidepressants were
helpful in increasing alcohol abstinence during the trial and reducing number of drinks consumed
on drinking days, which were robust findings when studies with high risk of bias were excluded
(35). However, there was not enough data to compare different antidepressants for this use.
A Cochrane review comparing antidepressants to placebo in the treatment of depression in
dementia populations found little to no difference in response as measured by scores on
depression rating scales in a 12-week time period, and unlikely any after six to nine months of
treatment (36). Of the 10 included studies, one of them (n=60) specifically compared
escitalopram to placebo and found similar results (37).
One study was excluded as it did not have enough data to compare antidepressants in patients
with end-stage kidney disease on dialysis (38).
9.3 PubMed Search
A PubMed search conducted October 2018 of “escitalopram,” “comparison,” and “depression”
yielded 238 abstracts. Of these, 65 were selected for relevance to the clinical treatment of
depression. An additional 39 were excluded for the following reasons: duplicates (13), no
included studies looking at escitalopram alone (10), outcomes only indirectly related to
depression (6), antidepressants as a switch or augmentation strategy (3), irrelevance (3), too
small (1), not comparing escitalopram to a placebo or an antidepressant (1), and poor design (2).
Review articles
1) A review paper from 2009 of 16 randomized controlled trials using the MADRS or HAMD
scales, published up to October 2007 (with some unpublished data), encompassing 4549 subjects
(escitalopram n=2272, SSRIs n=1750, SNRIs n=527), compared escitalopram to pooled SSRIs
and SNRIs after a treatment length of 8 weeks (39). The primary outcome was set at mean
treatment difference and secondary outcomes were defined as response rate (50% reduction in
26
MADRS from baseline) and remission rate (MADRS total score ≤ 12). The denominator of all
outcomes was set to be all patients who received at least one dose of the study medication
(n=4549), rather than all randomized patients (n=4602). While this may amplify results, as the
denominator is slightly smaller than the overall study population, it is likely a more accurate
measure of effect of study drug since it guarantees that participants actually did receive the study
medication. Separate analyses were conducted for escitalopram against all comparators, against
SSRIs, against SNRIs, and against placebo. Sensitivity analyses looking at the effect of trial
length and dose effect were also conducted.
Of the 16 included trials, 14 trials were included in Cipriani et al. 2018 network meta-analysis,
one was not (40), and one was Forest Laboratory data that could not be specifically located in the
reference list. Using data from all 16 trials, the authors estimated a small but significant mean
treatment difference of 1.1 points on the MADRS (95% CI: [0.6, 1.6], p < 0.0001) in favor of
escitalopram against all other comparators. With respect to response rate of escitalopram against
all other comparators, the odds ratio was 1.33 (95% CI: [1.15, 1.53], p < 0.0001), with similar
effect size for remission: OR 1.22, 95% CI: [1.06, 1.40], p = 0.0059.
The overall mean difference in treatment effect was very small, at 0.9 points (95% CI: [0.3, 1.5],
p=0.0023), but statistically significantly greater among patients treated with escitalopram
compared to the SSRIs (citalopram, fluoxetine, paroxetine, and sertraline). Response rate effect
was modest and statistically significant (OR 1.24 (95% CI: [1.06, 1.46], p=0.0089) though
remission rates did not significantly differ.
Against SNRIs (duloxetine and venlafaxine), the estimated mean treatment difference was higher
for escitalopram at 1.7 points (95% CI: [0.5, 2.8], p=0.0038), with a higher response difference
(OR 1.63, 95% CI: [1.23, 2.16], p=0.0007) and remission rate (OR 1.45, 95% CI: [1.10, 1.92],
p=0.0038).
The effect of escitalopram was largest in comparison to placebo (data from 5 trials), with an
estimated mean treatment difference of 2.3 MADRS points (95% CI: [1.4, 3.1], p < 0.0001).
Per sensitivity analyses, the mean treatment difference from four trials with longer study
durations (roughly 6 months) was modestly higher at 1.7 points (95%CI: [0.7, 2.6], p = 0.0005)
for all patients by the end of study period. The estimate at week 8, in those same studies, was
comparable to the above results at 1.1 points (95%CI: [0.2, 1.9], p = 0.0123). Five studies that
looked at a higher dose of escitalopram at 20 mg found a higher mean treatment difference of
2.0 points (95% CI: [1.1, 3.0], p < 0.0001.
The withdrawal rate due to adverse events was 5.4% for escitalopram and 7.9% for all
comparators (p=0.0007) which was primarily driven by significantly higher attrition rates in the
SNRI group (5.3% vs. 12.9%, p<0.0001), as the comparison to SSRIs was insignificant (5.4%
vs. 6.3%, p=0.2243). The total withdrawal rate was similar for SSRIs and for SNRIs as
withdrawal rate for adverse events.
27
All in all, escitalopram had a modest and significant advantage over pooled SSRIs and a
somewhat larger advantage over pooled SNRI data. Escitalopram appears to be considerably
more tolerable than the SNRIs.
2) A small review article of two double blinded trials (41), both of which were included in
Cipriani et al. 2018 (24), involving 491 participants studied treatment response and remission
differences between escitalopram and venlafaxine, finding a non-significant difference in
treatment response (OR 0.81 (95% CI 0.54, 1.22)) and remission (OR 0.90 (0.61, 1.34)) by the
end of a 7-8 week treatment period. This study was funded by Wyeth Pharmaceuticals, the maker
of venlafaxine.
3) A somewhat larger study analyzed four double blinded, placebo-controlled trials (42),
encompassing 1140 participants from the US with major depressive disorder, that used the
Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) and the MADRS for
assessment. After 8 weeks of treatment with escitalopram, 34% of the patient population
achieved Q-LES-Q scores within 10% of population norm as compared to 27% of those taking
placebo. There was a modest but significantly greater improvement in quality of life enjoyment
and satisfaction after 8 weeks of treatment with escitalopram (from 37.5±7.9 to 46.6±9.9) than
with placebo (from 37.3±7.8 to 44.2±10.6) (P<0.001, t value=4.05, d.f.=830). This study did not
compare change in MADRS score, treatment response or remission as measured by MADRS, in
the escitalopram arm compared to placebo arm.
4) An analysis of claims data from 2003-2005 of geriatric clients of the Health Care Information
Solutions (IHCIS) National Managed Care database, which includes medical and pharmacy
claims of over 25 million clients of over 35 health insurance plans from all census regions of the
United States (43). Endpoints included treatment persistence and hospitalization utilization, but
not treatment response or remission as measured by a depression rating scale. The study
identified 459 clients who received escitalopram against 1517 clients who received other
SSRIs/SNRIs over a 6-month treatment period. At baseline, escitalopram users were
significantly more likely to have comorbid generalized anxiety disorder (GAD), higher number
of baseline prescription drugs, higher mean prescription drug costs, and higher mean total
healthcare costs. Escitalopram users were less likely to discontinue their treatment as compared
to those on SSRI/SNRI using Chi-square testing (60.78 vs. 65.85%, p=0.047), which remained
significant after adjustment for baseline differences (Hazard Ratio 0.85, p=0.012). Time to index
therapy discontinuation, measured by Kaplan-Meier estimation, was also significantly longer in
patients treated with escitalopram, with a median time of 101 days for those on escitalopram and
92 days for those on an SSRI/SNRI (p=0.003). Though rate of hospitalization did not differ
between the two groups in the unadjusted nor adjusted analysis, the escitalopram group
appreciated 39% fewer hospitalization days, a significant finding only in the adjusted analysis
(p=0.004). Though the study did not compare treatment response or remission rates using a
depression rating scale, escitalopram users appeared to adhere to treatment longer, suggesting
better tolerability in this naturalistic, retrospective analysis.
The major limitation of this study is the use of pooled data, which obscures medications to which
escitalopram may be inferior or equivalent. For example, a meta-analysis comparing
escitalopram to SSRIs and SNRIs separately found a significantly higher discontinuation rate for
28
those on SNRIs but not for those on SSRIs, which drove an overall higher discontinuation rate
for the pooled SSRI/SNRI data (39). The results here may hide a similar effect.
A study by the same group did compare escitalopram users to specifically citalopram users with
similar methodology (44), finding that compared to those treated with citalopram (n=232),
clients taking escitalopram (n=459) were less likely to discontinue treatment (hazard ratio
[HR]=0.83, p=0.049) or switch to another second generation antidepressant (HR=0.62, p=0.001).
No other head-to-head trials were found.
5) A more recent study from 2011 analyzed pooled data from three randomized, double-blind,
multicenter trials from the US, comparing escitalopram (n = 462) to an SNRI (n = 467),
duloxetine or venlafaxine (45). Escitalopram treatment was associated with 41% higher odds of
depression remission at week 8 compared to SNRI treatment (p=0.0096). The study also found
that 41.6% of escitalopram treated patients compared to 48.0% of SNRI-treated patients
experienced adverse effects during the study period (p=0.0496). This study was funded by Forest
Research Institute.
6) A study that aimed to compare vortioxetine to a variety of different antidepressants, including
escitalopram, used effect sizes of study drug against placebo from “pivotal short-term double-
blind trials for vortioxetine and from publicly available sources for the pivotal short-term double-
blind trials” for other antidepressants as an indirect comparison (46). Efficacy outcomes were set
as response (50% reduction from baseline) as measured by MADRS or HDRS and the
tolerability outcome was discontinuation due to an adverse event, all over a 6-10 week treatment
period with preference for the 8-week timepoint. Three studies and additional data from
Lundbeck were included.
The response rate calculated for the pooled data for escitalopram was 53.1% as compared to
38.1% for placebo, a risk difference of 0.150 with 95% CI (0.091-0.209) with number needed to
treat (NNT) of 7 participants (95% CI: 5–11). The calculated risk difference and 95% CIs for
other drugs (vortioxetine, duloxetine, vilazodone, levomilnacipran, venlafaxine, and sertraline)
substantially overlapped with that of escitalopram. Discontinuation due to an adverse rate was
observed to be 5.2% in those on escitalopram as compared to 1.9% in the placebo group, with a
risk difference of 0.033 (95% CI: 0.011-0.054) and a number needed to harm (NNH) of 31 (95%
CI: 19-92). Here, the confidence intervals did not overlap with that calculated for sertraline (risk
difference 0.154, 95% CI (0.090-0.219)) nor venlafaxine (risk difference 0.128, 95% CI (0.092-
0.164), suggesting that perhaps escitalopram is more favorable with respect to discontinuation
rate due to adverse events. Given that the confidence intervals for NNT and NNH did not
overlap, it is unlikely that response and discontinuation due to adverse event are equally likely.
No statistical tests were done to compare these values.
In an effort to weigh the likelihood of response to the likelihood of discontinuation due to
adverse event, the authors calculated the likelihood to be helped or harmed (LHH) as measured
by the ratio of NNH to NNT. If LHH is >1.0, the patient is more likely to appreciate the
response. Escitalopram, with an LHH of 4.6 ranked second to vortioxetine (5.1), appeared
similar to duloxetine (4.3) and more substantially superior to vilazodone (3.30), levomilnacipran
(1.8), venlafaxine (1.4), and sertraline (1.2). No statistical tests were done to compare these
29
values. Notably, the pooled vortioxetine data amassed a total of 3008 patients, about 5 times
more than the total number of escitalopram patients (n=599). Unequal patient pool sizes may
explain some of the noted difference. Funding of this study was supported by Lundbeck.
Double-blinded RCTs
One double-blinded, randomized controlled trial was identified that was not included in the 2018
network meta-analysis (24) because it was published after January 2016 (47). In this 12-week
Romanian study of 287 participants randomized to either escitalopram or agomelatine, both
agents demonstrated significant improvement in the 17-item HDRS as compared to baseline but
no significant difference between groups. No funding sources were disclosed.
Single-blinded, non-randomized trials
A Taiwanese study of 302 patients were assigned to either escitalopram or paroxetine, based on
clinical judgment, in this single-blinded study for a treatment course of 8 weeks (48). Raters on
the scale of choice, the 21-item HAM-D, were blinded to the patients’ diagnoses and study
medications. The mean change in HAM-D21 was significantly more for escitalopram than
paroxetine at week 6 (-11.8 vs. -10.4 points) and 8 (-13.0 vs. -11.5 points respectively). Response
rates were also significantly different at 67.5% in the escitalopram group compared to 55.9% in
the paroxetine group (p<0.05 in both unadjusted and adjusted models for baseline HAM-D
scores) by the end of 8 weeks. Remission rates were not significantly different. The paroxetine
group was more likely to have adverse effects such as weakness (P<0.01), nausea and vomiting
(P<0.001), drowsiness (P<0.01), somnolence (P<0.01), and decreased appetite (P<0.05). This
was a non-industry funded study.
Open-label RCTs
Four studies comparing escitalopram to various other agents were open-label and randomized in
design. The largest study, an international study of 1008 patients, aimed to study differences in
cognitive performance between antidepressant groups and placebo (49). 1008 depressed patients
and 336 healthy controls were randomized to either escitalopram, sertraline, or venlafaxine (336
participants in each group). Over an 8-week period of treatment and repeated cognitive testing,
no change in cognition was found over time, testing, or treatment for any of the studied
medications.
A study of comparison between escitalopram as monotherapy and combination therapy, with and
without escitalopram, randomized 605 participants to escitalopram+placebo,
bupropion+escitalopram, and venlafaxine+mirtazapine such that the first medication in each pair
was open-label and the second medication was blinded to the participant (50). No significant
differences between groups were found with respect to remission or response rates as measured
by the QIDS-SR16 at neither 12 nor 28 weeks.
Finally, two small studies from India compared escitalopram to desvenlafaxine (51) and
agomelatine (52) in an open-label, randomized trial. The first study randomized 60 patients to
either escitalopram or desvenlafaxine and found that both arms demonstrated significantly
reduced HAM-D, HAM-A, and CGI scores from baseline but did not find significant between-
group differences on these measures (51) at the end of 6 weeks. The second study randomized 64
patients to escitalopram or agomelatine and compared group differences at the end of a 24-week
30
treatment period (52). 100% of patients exhibited a response (>=50% reduction in HAM-D17) in
both groups, with a significantly lower mean HAM-D17 score in the escitalopram group (4.41)
than in agomelatine group (5.87), though this is unlikely to be clinically meaningful as remission
was defined as scores <=7. No statistically significant differences with respect to adverse events
was found between groups. The open-label design with no placebo control makes it unlikely that
this study would find significant, meaningful differences between the two drugs.
Observational
One Spanish observational, multicenter, retrospective study conducted using computerized
medical records gathered data from 965 patients taking escitalopram (n=131), citalopram
(n=491), or venlafaxine (n=343) between 2003-2007 with a follow-up period of at least 18
months. The authors defined remission as completion of 6 months of pharmacotherapy and found
that the concordance of this proxy measurement with documentation of remission (undefined)
per chart review in a random sampling yielded 91.7%. Since it is not clear how remission was
documented in the chart, the meaning of this concordance measurement, and therefore the
validity of the authors’ proxy measurement of remission as completion of 6 months of
pharmacotherapy, is unclear. The authors found that escitalopram-treated patients achieved
higher remission rates compared to citalopram (58.0% vs. 38.3%) and venlafaxine-treated
patients (32.4%), p < 0.001. However, the escitalopram group at baseline was younger, male-
dominated, with less co-morbidity compared to the other two groups. The study did not attempt
to correct for these baseline differences before assessing for statistical significance between
different remission rates. This study was funded by Lundbeck.
Expert opinion
Finally, an expert consensus meeting was held in 2007, funded by Lundbeck, in which
depression experts from multiple countries amassed published evidence from randomized
controlled trials and meta-analyses, designating fair comparison RCTs as "Class A" evidence and
meta-analyses as "Class B" evidence, given post hoc design such that the data generates the
hypothesis rather than confirms it. The authors define “definite superiority” of a medication if
there is evidence of its superiority on the primary efficacy measure from two pivotal studies
under conditions of fair comparison at approved doses of the studied medications or if there is
one such pivotal study supported consistently by meta-analyses. It is not clear from the article
what constitutes a “fair comparison.” The authors specifically looked at clomipramine,
duloxetine, escitalopram, milnacipran, mirtazapine, and venlafaxine “on the basis of published
claims” that they may be superior in efficacy to other medications.
Several variables were taken into consideration when determining the quality of the study: the
validity of the outcome variable (ex. change in depression scale scores), the usefulness of
reported clinical measures like response and remission, the statistical methods, the time course of
response, the decision to pool data as opposed to conducting meta-analyses, and breakdown of
subtypes or subgroups of patients.
Relevant to escitalopram, the authors identified two fair comparison RCTs, “Class A evidence”
in favor of 20 mg escitalopram over 40 mg citalopram (53) and over 40 mg paroxetine (54), both
of which were included in Cipriani et al. 2018 meta-analysis (24) and Kennedy et. al 2009 (39)
reviewed earlier in this section. The article also identified several meta-analyses, or “Class B”
31
evidence, that favored escitalopram over citalopram (55–57). Finally, they identified the
aforementioned meta-analysis by Kennedy, et al. (39) as reasonable Class B evidence in favor of
escitalopram over all comparators tested. Given the above criteria, the article identified
escitalopram, clomipramine, and venlafaxine as being of "definite superior efficacy" in treatment
of moderate-to-severe depression.
The overall merit of this study is uncertain, given that the meeting itself was funded by
Lundbeck, the pharmaceutical company behind branded escitalopram, and given somewhat
arbitrary criteria for the designation of “definite superior efficacy.” Additionally, no statistical
methodology was involved in this publication. However, this article does represent the expert
consensus on the treatment of depression.
SUMMARY
In summary, the bulk of the argument in favor of escitalopram as an efficacious treatment for
depression over several other available agents, is derived from a major, network meta-analysis of
522 randomized controlled trials incorporating GRADE evidence, that designates escitalopram
as a highly performing drug both on measures of efficacy and tolerability (24). The issue of
tolerability is particularly important as antidepressants take several weeks to take maximal effect;
thus a more tolerable drug is more likely to be adhered to long enough to witness an
antidepressant effect. On measures of efficacy in head-to-head trials as compared to members of
its class, SSRIs, escitalopram appears to be statistically significantly superior to citalopram,
fluoxetine, and fluvoxamine, and non-statistically significantly superior to paroxetine and
sertraline. With respect to acceptability, escitalopram appears to be statistically significantly
superior to fluvoxamine and non-statistically significantly superior to all others.
A meta-analysis by the same group looking at escitalopram compared to other agents largely
confirmed those findings, and provided more detail about specific adverse events (26).
Escitalopram was generally a very well tolerated drug, appearing equally or, in the case of
bupropion, sertraline, and duloxetine, less likely to experience side effects.
Other review articles by different authors (39,41), but of RCTs included in Cipriani et al. 2018
(24), confirmed similar results of escitalopram superiority on measures of efficacy and drop-out
rates, particularly in comparison to SNRIs.
Other forms of evidence, including retrospective analyses of claims data (44,58), single-blinded
trials allocating patients to treatment by clinical judgment (48), open-label randomized trials
(49–52), and retrospective, observational data (59) either found statistically significant benefit to
escitalopram on a variety of measures, including response and remission rates and likelihood of
treatment withdrawal, or equivalence to comparators. One paper delineating expert consensus
was also support the superiority of escitalopram over other antidepressants (60). Of note, none of
the references found superiority of another drug over escitalopram, including articles that had
funding from the comparator pharmaceutical agency, which may introduce bias in favor of the
comparator.
In conclusion, escitalopram demonstrates high performance on measures of efficacy and
tolerability that is at best superior to most other available antidepressants and at worst, equivalent
32
to several available antidepressants. The body of evidence supporting this notion is robust, not
only from very large network meta-analysis of double blinded randomized controlled trials, but
also from other data sources as aforementioned.
33
10. Summary of comparative evidence on escitalopram safety
A systematic review was conducted using Cochrane and PubMed databases (last search
November 2018). The keyword “escitalopram” was used for the Cochrane search. The keywords
“escitalopram” and “safety” were used for the PubMed search. There were no language
requirements.
The initial search yielded 15 reviews in Cochrane and 422 abstracts (including Cochrane
reviews) in PubMed. The abstracts were narrowed down to 368 based on publication date;
articles published prior to 2002 (year of escitalopram FDA approval) were excluded considering
they would have been considered in the FDA approval process and then subsequent Cochrane
reviews. After excluding irrelevant article types (i.e. interview, personal narrative, etc.), 194
abstracts remained and were reviewed. Of those 194 abstracts, 122 were excluded for limited
relevance in evaluating escitalopram comparative safety (i.e. primarily comparative study for
citalopram without evaluating escitalopram or did not comment adequately on safety),
inadequate sample size, study design of insufficient quality, and/or data availability limitations.
Of note, an additional 12 publications that were identified by hand-search and reference-
checking were included in the safety evaluation. As a result, 40 published works are considered
in the escitalopram safety assessment below (with a smaller proportion directly cited in the main
text).
10.1 Estimate of Total Patient Exposure to Date The United States Food and Drug Administration first approved escitalopram for use in patients
in August 2002 (61). No data are currently available for worldwide total exposure to
escitalopram. In the US, mental health prescriptions are in the top 3 of all prescriptions,
increasing from just over 300 million in 2012 to nearly 400 million dispensed prescriptions in
2016 (62). Regarding specific prescribing for escitalopram, from 2006-2016, the number of US
prescriptions have ranged from just under 17 million (2013) to nearly 27.5 million (2006) per
year, including approximately 25.2 million in 2016 and achieving a ranking of 26th
of all
prescribed medications in the US (13). Also, escitalopram is one of the most commonly
prescribed antidepressant medications (often in the top 5 annually) in the United States (13).
To get a better sense of global patient use, a number of retrospective international articles on
usage trends were reviewed. An article on prescription patterns of antidepressants in five tertiary
care psychiatric centers in India (n = 312 patients) noted that the majority of patients were
prescribed SSRIs (n = 194), with the caveat that many were for non-depression diagnoses, and
that escitalopram (n = 114) was the most commonly used medication (63). Another study from
India on prescribing patterns at 11 centers (n = 4480 patients) found that the most commonly
prescribed antidepressant was escitalopram (n = 951 of 2816 patients on antidepressants) (17).
An article on antidepressant prescriptions in children and adolescents in China treated at 40
psychiatric centers (n = 109 patients) indicated that escitalopram (n = 14 patients), sertraline
(n=24), and fluoxetine (n = 41) were the most commonly prescribed antidepressants (64). In
another study of Asian patients (n = 370), escitalopram and mirtazapine (20% each) were the
most commonly prescribed antidepressants for patients with a medical co-morbidity (65). In a
study on SSRI and SNRI use in Italy from 2003-2009 (n = nearly 1,000,000 patients),
escitalopram had the greatest increase in prevalence of use (nearly 3% increase) and highest
34
frequency of participants on antidepressants with good adherence to their medication regimen
(28.5%) (66). In a study on prescribing patterns for antidepressants in Italian primary care,
SSRIs, particularly escitalopram (n = 253 on escitalopram out of 1377 total), were the most
commonly prescribed antidepressant medications (67). In a Danish study evaluating prescribing
patterns in 2009-2010, escitalopram was more commonly chosen as the first SSRI over
citalopram and sertraline (n = 65,313 prescriptions for treatment-naïve patients, 19% of which
were for escitalopram with higher rates when psychiatrists and hospital physicians were the
prescribers) (22). These studies indicate the international popularity of escitalopram.
10.2 Common Adverse Effects and Frequency Estimates (68–70)
The most common side effects (per epocrates (69), affecting at least 2% of people on
escitalopram at recommended doses) include headache, nausea, sexual dysfunction (ejaculatory
dysfunction, decreased libido, anorgasmia, and impotence), sleep disruption (somnolence,
insomnia, abnormal dreams, yawning, and daytime sedation), xerostomia, gastrointestinal
disruption (diarrhea, constipation, anorexia, increased appetite, vomiting, dyspepsia, and
abdominal pain), fatigue, diaphoresis, dizziness, flu-like syndrome, menstrual disorder,
paresthesia, rhinorrhea, sneezing, blurred vision, rash or itching, tremor, and emotional blunting.
Serious side effects include suicidality, worsening depression, (hypo)manic conversion, cardiac
effects (QT prolongation and torsades de pointes), serotonin syndrome, hematologic changes
(abnormal bleeding and altered platelet function), allergic reactions (anaphylaxis, Stevens-
Johnson syndrome, and toxic epidermal necrolysis), acute-closure glaucoma, seizures,
hyponatremia, priapism, extrapyramidal symptoms and withdrawal symptoms in the event of
abrupt discontinuation.
Depression
Comparison with other SSRIs In a Cochrane review comparing escitalopram to other antidepressant medications in major
depressive disorder, fourteen multicenter, randomized control trials (RCTs) with double-blinding
compared escitalopram to another SSRI (n = mean of 280 subjects/study with range of 30-459)
(26). They demonstrated that escitalopram did not have significantly different rates of mild to
severe adverse events than citalopram (n = 1802 in 6 RCTs), fluoxetine (n = 804 in 4 RCTs), or
paroxetine (n = 784 in 2 RCTs). Also, there was no significant difference in serious adverse
events for escitalopram compared to sertraline (n = 483 in 2 RCTs); however, escitalopram had a
decreased incidence of diarrhea. Of note, a limitation of this review is that the majority of the
included studies failed to fully describe the allocation process, although they appeared to have
similarities in their design and conduct. Unless otherwise noted above, escitalopram and other
SSRIs had similar rates of agitation, anxiety, constipation, diarrhea, dry mouth, hypotension,
insomnia, nausea, urinary complaints, drowsiness, vomiting, deaths, suicide, suicidality, and
other adverse events (such as jitteriness, fatigue, flu-like syndrome, headache, impotence,
decreased libido, pain, and increased sweating or yawning).
In a more recent systematic review and network meta-analysis of double-blinded RCTs in major
depression (n = 116,447 patients, 522 RCTs between 1979-2016) comparing 21 antidepressants
or placebo, escitalopram (moderate evidence grade) was among the most tolerated
35
antidepressants according to low drop-out rates for participants taking escitalopram (24). The
other similarly well tolerated SSRIs included citalopram, fluoxetine, and sertraline. Also
providing evidence of escitalopram tolerability, retrospective claims analysis of antidepressant
persistence from 2002-2005 in the US (n = 43,921) demonstrated that people who had started on
escitalopram (compared to citalopram, fluoxetine, and paroxetine) were more likely to have
continued the medication and less likely to require augmentation at 2 and 6 months of treatment
(71).
In an older review of RCTs from before 2007 (n = >4000 escitalopram treated patients), none of
the escitalopram-treated patients attempted suicide or had higher suicidal behavior or thoughts
than placebo (72). Also, while escitalopram had higher sexual dysfunction adverse events than
paroxetine, it was comparable to citalopram.
Escitalopram has a fairly similar side effect profile to its closely related citalopram based on
multiple studies, including a French RCT performed in the primary care setting (n = 357) (73)
and a multicenter Chinese RCT (n = 240) (28). Of note, an open-label pilot study on
escitalopram doses up to 50 mg in patients who had not responded to adequate citalopram
treatment (n = 42), there was no increase in serious adverse events, while there was a dose-
related decrease in tolerability (increased headache, nausea, diarrhea, and nasopharyngitis) for
doses higher than the typically prescribed 10-20 mg (74).
Comparison with other classes of antidepressant medications
In a Cochrane review comparing escitalopram to other antidepressant medications in major
depressive disorder, eight RCTs compared escitalopram to newer antidepressant medications (i.e.
SNRIs; n = mean of 307 subjects/study with range of 202-547) (26). Regarding serious adverse
events, there was no significant difference between escitalopram and bupropion (n = 822 in 3
RCTs), duloxetine (n = 1111 in 3 RCTs), or venlafaxine (n = 487 in 2 RCTs). Regarding mild to
moderate adverse events, escitalopram was associated with lower rates of constipation (n = 557
in 2 RCTs), dry mouth, and insomnia (n = 822) and a higher rate of fatigue and yawning (n =
557) than bupropion; less dry mouth, nausea, and dizziness (n = 1111) compared to duloxetine;
and lower rates of nausea and sweating than venlafaxine (n = 487). The incidence for other mild
to moderate side effects were comparable between escitalopram and the other newer
antidepressants.
In a more recent systematic review and network meta-analysis of double-blinded RCTs in major
depression (n = 116,447 patients, 522 RCTs between 1979-2016) comparing 21 antidepressants
or placebo, as noted above, escitalopram (moderate evidence grade) was among the most
tolerated antidepressants (24). The other similarly well tolerated newer antidepressants included
agomelatine and vortioxetine; by contrast, amitriptyline, clomipramine, duloxetine, fluvoxamine,
reboxetine, trazodone, and venlafaxine were among the most poorly tolerated antidepressants
based on their high drop-out rates.
In a multicenter (29 sites), double-blind, randomized Romanian study (n = 417) comparing
agomelatine with escitalopram, there were overall similar incidences of adverse events, though
escitalopram was associated with higher levels of gastrointestinal disturbance (nausea, vomiting,
abdominal pain, and diarrhea) (47).
36
Comparison with placebo In a Cochrane review comparing escitalopram to other antidepressant medications in major
depressive disorder, nine RCTs included comparisons with placebo; however, the focus of the
review was on comparison between active medications and did not include detailed placebo
analysis (26).
In 2011, the FDA announced high doses of citalopram could prolong the QT interval;
subsequently, the European Medicines Agency also issued an alert for escitalopram. In an Italian
observation study of 35 psychiatric services over a 3-month period (n = 426 patients), citalopram
increased the QTc, while escitalopram did not significantly increase the QTc (75). Although the
cross-sectional study design has limitations, the evaluated measures were objective and
supported by multiple centers. In a large (n = 3298), double-blind placebo-controlled RCT study
of escitalopram’s cardiovascular toxicity profile, escitalopram affected heart rate without
significantly altering other cardiologic parameters or increasing cardiac-associated adverse
events (76).
In a placebo-controlled, double-blinded RCT on escitalopram use in heart failure patients (n =
372) over a median time of > 18 months, there was no difference in serious adverse effects,
except that the placebo group had higher rates of worsening depression. Also, there were slightly
higher dropout rates in the escitalopram group, usually occurring within the first 6 weeks (77). In
two placebo-controlled RCTs evaluating escitalopram use in acute coronary syndrome patients
(n = 217 (78) and n = 240 (79)), there was no difference in serious adverse events or major safety
measures with escitalopram treatment, although the first study had slightly higher rates of
dizziness with escitalopram treatment.
In double-blind, placebo-controlled RCTs of chronic hepatitis C patients with interferon-
alpha/ribavirin-associated depression (n = 389 in 3 RCTs), the escitalopram group had fewer
respiratory problems and a higher rate of dizziness; otherwise, there were no major differences in
the side effect profiles (80). In a multicenter (21 hospitals in Germany), double-blind placebo-
controlled RCT on depression in HCV patients (n = 181 patients without a prior psychiatric
history) undergoing IFN treatment, there was no difference in the tolerability and safety between
the groups beyond a slightly higher incidence of adverse events in the placebo group (81).
Anxiety
Escitalopram was approved by the FDA for use in generalized anxiety disorder in December
2003.
In a 2011 meta-analysis of 3 RCTs (n = 1388) (82) and a 2005 older pooled results analysis of 3
similarly designed double-blind RCTs (n = 850) (83) comparing escitalopram versus placebo in
generalized anxiety disorder, escitalopram had significantly higher rates of anorgasmia, fatigue,
and diarrhea in the meta-analysis with the addition of increased nausea, ejaculation disorder (in
males), decreased libido, and insomnia in the pooled results analysis.
37
In a more recent meta-analysis of three placebo-controlled RCTs (n = 1598) on escitalopram use
in social anxiety disorder, the overall withdrawal rates (often for mild to moderate adverse
events) were higher for escitalopram than placebo, though the withdrawal rates were more
comparable in a flexible dose study (84).
In a double-blind RCT comparing escitalopram, citalopram, and placebo use in panic disorder (n
= 366), adverse events in the escitalopram and placebo groups were comparable (85).
Special populations
Children and adolescents
In a 2018 review of RCTs published on antidepressant use in depressed pediatric patients, 7
RCTs were identified, 2 of which compared escitalopram to placebo (n = 312 in an acute-phase
study and 165 in an extension study) (86). While there have been concerns about the potential for
increased suicidality with SSRI treatment, neither RCT found an increase in suicidality with
escitalopram. The most common side effects were generally rated as mild/moderate and were of
a similar type to those reported for adults.
In a placebo-controlled, double-blinded RCT of escitalopram treatment for pediatric depression
(n = 268), the escitalopram rates of adverse events were similar to placebo (87).
In a retrospective, new-user cohort study based on paid health insurance claim data (1997-2009,
n = 11,3714 on SSRIs out of 50 million covered patients) provided by an IMS unit, Lifelink (88),
escitalopram and citalopram had the highest crude incidence of ventricular arrhythmia, cardiac
arrest, or sudden cardiac death, while fluoxetine had the lowest incidence. Of note, these events
were fairly rare (total of 40 for all subjects).
Pregnant and lactating women
A 2012 review evaluated escitalopram use in pregnancy and breastfeeding, which included data
from 5 cohort studies (2 prospective and 3 retrospective), 1 case-control study, and 5 case-reports
(89). Four studies reported on major malformations with escitalopram use, which had incidence
rates that were within the range for the general population. One prospective cohort study
reported an increase in perinatal complications (lower live birth rates, low birth weight infants,
and higher rates of spontaneous abortion) compared to placebo, albeit with no difference
compared to other antidepressants. Regarding safety in breastfeeding, no adverse events have
been reported for the fewer than 50 exposed cases reported in the literature at the time of the
review. Overall, few studies have focused on the escitalopram safety profile during these life
events and the studies included in this review have significant design heterogeneity while none
satisfied the recommended methodological criteria for assessing teratogenicity of drugs.
Based on a 2015 review of SSRI use during breastfeeding, there are limited data on escitalopram
safety in the postpartum period (n = 8 publications, some case reports, on 37 neonates) (90).
Only one neonate was reported to have a serious adverse event, necrotizing enterocolitis at day 5
of life. Of note, based on a total of 22 studies for sertraline (n = 279 cases, including one RCT),
sertraline (along with paroxetine) is recommended for using during breastfeeding, while
fluoxetine, citalopram, and duloxetine are not recommended as first-line therapy.
38
Geriatric and aging population
With consideration of the problematic risk of falls in the elderly, a network meta-analysis
compared the chance of an adverse event (dizziness) that could increase fall risk with various
antidepressants (n = 4588), which included escitalopram in two of the fifteen studies (91). While
duloxetine and venlafaxine had high risks of increasing dizziness, escitalopram carried an
intermediate risk (comparable with citalopram and paroxetine) that was slightly higher than that
for sertraline and fluoxetine.
In an extension study of a placebo-controlled RCT evaluating escitalopram in elderly patients (n
= 225), the most common adverse events with escitalopram were accidental injury, rhinitis,
increase in weight, and arthralgia (92). A major limitation of this extension study is that it lacked
a placebo group and the common adverse events observed with escitalopram probably also have
a non-zero incidence in elderly patients.
In a randomized, placebo-controlled trial of elderly patients with generalized anxiety disorder (n
= 177), patients taking escitalopram had higher rates of fatigue, somnolence, and urinary
symptoms; of note, the greatest difference in adverse event reporting between escitalopram and
placebo was in the week when the escitalopram dose was doubled (93).
SUMMARY
Based on the evidence above, escitalopram is at least as safe, if not safer, than amitriptyline and
fluoxetine. Based on a 2018 systematic review and network meta-analysis of 522 RCTs,
escitalopram is among the most-tolerated antidepressant medications. It was comparable to
fluoxetine, but much more tolerated than amitriptyline. Furthermore, it is internationally popular
with high reported adherence rates in countries like Italy. Escitalopram has a similar side effect
profile to many other SSRIs when studied in depression and anxiety, including gastrointestinal
symptoms and sexual dysfunction, which are often rated as mild to moderate and are not known
to increase morbidity or mortality.
Regarding more serious adverse events, there has been concern about QTc prolongation with
citalopram that was also sometimes applied to escitalopram, especially in Europe. In the
pediatric population, there was a higher rate of cardiac events with escitalopram than placebo
with the caveat that cardiac events were a very rare occurrence in this population. There is even
greater support in the literature that escitalopram is well-tolerated from a cardiovascular
perspective, including in patients with recent acute coronary syndrome, heart failure, and chronic
hepatitis diagnoses.
With respect to special populations, escitalopram and placebo treatment do not have any
difference in suicidality in the pediatric population. While there are limited data in pregnant and
breastfeeding patients with significant limitations in study design and sample sizes, escitalopram
has been fairly safe in that population. For geriatric patients, a major concern is the reported
increase in dizziness, which has also been observed in younger patients. However, the dizziness
increase is only an intermediate increase based on network meta-analysis (lower than SNRIs,
higher than sertraline and fluoxetine, and comparable to other SSRIs). More importantly, there
39
has been no reported increase in serious adverse events with escitalopram treatment in geriatric
patients.
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pegylated interferon alfa-2a-induced depression in hepatitis C: a 12-week, randomized, double-blind,
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a meta-analysis of prospective comparative studies. Pharmacoepidemiol Drug Saf, 14(12), 823-7.
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randomized, double-blind, placebo-controlled extension trial. J Child Adolesc Psychopharmacol, 23(7),
468-80. doi:10.1089/cap.2012.0023
Grant JE, Potenza MN. (2006). Escitalopram treatment of pathological gambling with co-occurring
anxiety: an open-label pilot study with double-blind discontinuation. Int Clin Psychopharmacol,
21(4):203-9. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16687991
Guerdjikova AI, McElroy SL, Kotwal R, et al. (2008). High-dose escitalopram in the treatment of binge-
eating disorder with obesity: a placebo-controlled monotherapy trial. Hum Psychopharmacol, 23(1):1-11.
Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18058852
Isolan L, Pheula G, Salum GA Jr, et al. (2007) An open-label trial of escitalopram in children and
adolescents with social anxiety disorder. J Child Adolesc Psychopharmacol, 17(6), 751-60.
doi:10.1089/cap.2007.0007
Khan A, Bose A, Alexopoulos GS, et al. (2007). Double-blind comparison of escitalopram and duloxetine
in the acute treatment of major depressive disorder. Clin Drug Investig, 27(7), 481-92. Retrieved from
https://www.ncbi.nlm.nih.gov/pubmed/17563128
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. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17453659
41
Klieger-Grossmann C, Weitzner B, Panchaud A, et al. (2011). Pregnancy outcomes following use of
escitalopram: a prospective comparative cohort study. J Clin Pharmacol, 52(5):766-70.
doi:10.1177/0091270011405524
Leone MA, Vigna-Taglianti F, Avanzi G, et al. (2010). Gamma-hydroxybutyrate (GHB) for treatment of
alcohol withdrawal and prevention of relapses. Cochrane Database Syst Rev, (2), CD006266.
doi:10.1002/14651858.CD006266.pub2
Lin HL, Hsu YT, Liu CY, et al. (2013) Comparison of escitalopram and paroxetine in the treatment of
major depressive disorder. Int Clin Psychopharmacol, 28(6), 339-45.
doi:10.1097/YIC.0b013e32836458e2
Maity N, Ghosal MK, Gupta A, et al. (2014). Clinical effectiveness and safety of escitalopram and
desvenlafaxine in patients of depression with anxiety: a randomized, open-label controlled trial. Indian J
Pharmacol, 46(4), 433-7. doi:10.4103/0253-7613.135959
Mancini M, Gianni W, Rossi A, et al. (2009). Duloxetine in the management of elderly patients with
major depressive disorder: an analysis of published data. Expert Opin Pharmacother, 10(5), 847-60.
doi:10.1517/14656560902806431
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premenstrual syndrome. Cochrane Database Syst Rev, (6), CD001396.
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duloxetine 60 mg for the treatment of chronic low back pain. Expert Opin
Pharmacother, 11(7):1049-52. doi:10.1517/14656561003730413
Merideth C, Cutler AJ, She F, et al. (2012). Efficacy and tolerability of extended release quetiapine
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doi:10.1097/YIC.0b013ed32834d9f49
Muhonen LH, Lönnqvist J, Juva K, et al. (2008). Double-blind, randomized comparison of memantine
and escitalopram for the treatment of major depressive disorder comorbid with alcohol dependence. J
Clin Psychiatry, 69(3), 392-9. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18348597
Muller JE, Wentzel I, Koen L, et al. (2008). Escitalopram in the treatment of multisomatoform disorder: a
double-blind, placebo-controlled trial. Int Clin Psychopharmacol, 23(1), 43-8. Retrieved from
https://www.ncbi.nlm.nih.gov/pubmed/18090507
Pigott TA, Prakash A, Arnold LM, et al. (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.
Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17559729
Rampello L, Alvano A, Raffaele R, et al. (2006). New possibilities of treatment for panic attacks in
elderly patients: escitalopram versus citalopram. J Clin Psychopharmacol, 26(1):67-70. Retrieved from
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42
Rao V, Spiro JR, Rosenberg PB, et al. (2006). An open-label study of escitalopram (Lexapro) for the
treatment of 'Depression of Alzheimer's disease' (dAD). Int J Geriatr Psychiatry, 21(3), 273-4. Retrieved
from https://www.ncbi.nlm.nih.gov/pubmed/16477587
Rapaport MH, Bose A, Zheng H. (2004). Escitalopram continuation treatment prevents relapse of
depressive episodes. J Clin Psychiatry, 65(1), 44-9. Retrieved from
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Raskin J, George T, Granger RE, et al. (2012). Apathy in currently nondepressed patients treated with a
SSRI for a major depressive episode: outcomes following randomized switch to either duloxetine or
escitalopram. J Psychiatr Res, 46 (5), 667-74. doi:10.1016/j.jpsychires.2012.02.010
Robert S, Hamner MB, Ulmer HG, et al. (2006). Open-label trial of escitalopram in the treatment of
posttraumatic stress disorder. J Clin Psychiatry, 67(10), 1522-6. Retrieved from
https://www.ncbi.nlm.nih.gov/pubmed/17107242
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double-blind, placebo-controlled, fixed-dose, randomized study. J Clin Psychopharmacol, 27(5), 444-50.
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of intravenous citalopram in patients with major depressive disorder. Neuropsychobiology, 54(4), 201-7.
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Soares CN, Thase ME, Clayton A, et al. (2010). Desvenlafaxine and escitalopram for the treatment
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therapy: results from a clinical trial of duloxetine. Ann Clin Psychiatry, 17(4), 259-68.
doi:10.1080/10401230500296402
43
11. Comparative cost and cost-effectiveness
11.1 Comparative cost
As cost information was not available through the International Medical Products Price Guide1,
managed by Management Sciences for Health (MSH), drug pricing was obtained manually
through search of WHO’s list of price sources2 and personal contact with all suppliers listed in
the MSH guide3. Listed costs are in the original country currency for the package listed.
Exchange rates to U.S. Dollars (USD) were calculated manually with rates as updated as October
2018. The cited links were all last accessed in November 2018.
Country Number of
Pills
Pill Dosage
(mg)
Listed cost Cost in USD Cost/pill in
USD
Australia4 28 10 19.11 AUD $13.61 $0.49
Belgium5 56 10 €12.66 $14.58 $0.26
Czech Republic6 28 10 67.57 CZK $3.02 $0.11
Denmark7 1 10 0.08 DKK N/A $0.09
Estonia8 28 10 €3.08 $3.55 $0.13
Finland9 30 10 €1.99 $2.30 $0.08
Lebanon10
28 10 9761 LBP $6.44 $0.23
Malaysia11
1 10 2.50 MYR N/A $0.60
Netherlands12
15 10 €0.40 $0.45 $0.03
Norway13
28 10 73.30 NOK $8.97 $0.32
Philippines14
1 10 4.91 PHP N/A $0.09
Sweden15
28 10 45.6 SEK $5.10 $0.18
1 http://mshpriceguide.org/en/home/
2 http://www.who.int/medicines/areas/access/med_price_info_sources/en/
3 http://mshpriceguide.org/en/list-of-addresses/?menuNo=16
4 http://www.pbs.gov.au/medicine/item/8700X-9432K
5 http://www.cbip.be/fr/chapters/11?frag=8177&view=pvt&vmp_group=11171
6 http://www.sukl.eu/sukl/seznam-cen-a-uhrad-lp-pzlu-k-1-10-2018
7 https://www.medicinpriser.dk/default.aspx?lng=2
8 http://ravimiregister.ravimiamet.ee/en/default.aspx?pv=HumRavimid.Ravim&vid=a09226e1-4174-4dae-ab7d-
e7223d132545 9 https://asiointi.kela.fi/laakekys_app/LaakekysApplication/Valmisteet?sarake=Vhinta&jarjestys=asc
10 https://www.moph.gov.lb/en/Drugs/index/3/4848/lebanon-national-drug-index-lndi-
11 https://www.pharmacy.gov.my/v2/en/apps/drug-price
12
https://www.medicijnkosten.nl/databank?zoekterm=ESCITALOPRAM&toedieningsvorm=TABLETTEN%20EN%
20CAPSULES 13
https://www.legemiddelsok.no/sider/default.aspx?searchquery=escitalopram&f=Han;MtI;Vir;ATC;Var;Mar;Mid;Av
r;gen;par;&pane=0# 14
https://dpri.doh.gov.ph/index.php?page=druginfo&c=false&dyear=2015&druginfo=ESCIT00181TAB4900013&dru
gcode=ESCIT 15
https://www.tlv.se/beslut/sok-i-databasen.html?product=escitalopram&tab=1
44
The following data was made available through personal communications:
Missionpharma (French company, suppliers to Africa): provided the following list of several
prices available in India as well as two from the UK.
Product Name
Stren
gth
Uni
ts
For
m
Pric
e
Curre
ncy
Price in
USD*
Price per Tablet in
USD* Alwel - Zuventus (Zuvista)
[Escitalopram]
10
MG 10
Tab
s 53 INR $0,72 $0,0721
Ambulax-Ad - Unimarck
[Escitalopram]
10
MG 10
Tab
s 60 INR $0,82 $0,0816
Articalm - Cadila (Vibra)
[Escitalopram]
10
MG 10
Tab
s 57 INR $0,78 $0,0776
C-Pram-S - Unichem [Escitalopram]
10
MG 10
Tab
s 68 INR $0,93 $0,0925
Censpram - USV [Escitalopram]
10
MG 10
Tab
s 62 INR $0,84 $0,0844
Censpram - USV [Escitalopram]
10
MG 10
Tab
s 57,4 INR $0,78 $0,0781
Cita-S - Crescent [Escitalopram]
10
MG 10
Tab
s 57,8 INR $0,79 $0,0786
Citalop-S - RPG (Sertec)
[Escitalopram]
10
MG 10
Tab
s 53 INR $0,72 $0,0721
Citel - Mankind (Magnet)
[Escitalopram]
10
MG 10
Tab
s
62,9
6 INR $0,86 $0,0857
Citofast - Glenmark [Escitalopram]
10
MG 10
Tab
s 79 INR $1,07 $0,1075
Deplam-S - Mankind (Discovery)
[Escitalopram]
10
MG 10
Tab
s 39,9 INR $0,54 $0,0543
Deptune - Baroda [Escitalopram]
10
MG 10
Tab
s 51 INR $0,69 $0,0694
Dipwell[New] - Dycine
[Escitalopram]
10
MG 10
Tab
s 60 INR $0,82 $0,0816
Duram - Daksh [Escitalopram]
10
MG 10
Tab
s 63 INR $0,86 $0,0857
Ecitalop - East West [Escitalopram]
10
MG 10
Tab
s 55,6 INR $0,76 $0,0756
Elcit - Elite Pharma [Escitalopram]
10
MG 10
Tab
s 52 INR $0,71 $0,0708
Escimax - Invision (Marx)
[Escitalopram]
10
MG 10
Tab
s 55 INR $0,75 $0,0748
Escin - Cinerea [Escitalopram]
10
MG 100
Tab
s 690 INR $9,39 $0,0939
Escipra - Mesmer (Icon)
[Escitalopram]
10
MG 10
Tab
s 67 INR $0,91 $0,0912
Escita - Mediez Pharma
[Escitalopram]
10
MG 10
Tab
s 62 INR $0,84 $0,0844
Cipralex - Lundbeck [Escitalopram]
10
MG 7
Tab
s
113,
65 INR $1,55 $0,2209
Cipralex - Lundbeck [Escitalopram]
10
MG 28
Tab
s
14,9
1 GBP $19,38 $0,6921
Escitalopram (Non – proprietary)
10
MG 28
Tab
s
14,5
5 GBP $18,91 $0,6754
* INR/USD and GDP/USD exchange rates as on 23/10/2018
45
Durbin PLC (UK): a 28-tablet pack of 10 mg escitalopram is available for £2.50, corresponding
to $3.28, or $0.12 per pill.
IMRES (Netherlands): Escitalopram is currently sourced from the EU registered generic
company Sandoz at USD $1.45 for a pack of 28 tablets, corresponding to $0.05 per pill.
11.2 Cost-effectiveness
A search of the Cochrane database for the keyword “escitalopram” yielded 15 Cochrane reviews.
Of these, 7 were excluded for irrelevance to depression, and the remaining 8 were excluded for
irrelevance to cost-effectiveness.
A search of PubMed for the keywords “escitalopram” and “cost effectiveness” yielded 84 results.
Of these, 38 publications were selected for relevance of escitalopram for the treatment of
depression that reported cost data by drug administered. On closer review, 8 were excluded for:
small sample size (1), poor methodology (1), cost data was obtained by parity from another drug
(escitalopram was not marketed in the country at the time of study) (2), review of studies that
were already included in more recent reviews included here (1), and duplicates (3). A search of
the Cochrane Database of Systematic Reviews yielded no additional studies.
The following reflects the findings from a total of 30 publications. Of those 30, seven were
reviewed in one or more of the cited reviews below. These were separately reviewed, and as the
authors here largely agree with the findings presented in the review articles, are not additionally
reviewed in this text.
Review articles Of the remaining 23 publications, three were review articles. The largest review, published in
2005, included 12 studies, from Sweden, Finland, Norway, Germany, Austria, Netherlands,
Belgium, the UK, and the US (1). Eleven of these studies were modeling analyses while one was
a prospective multinational analysis, which included data from UK, Germany, France, Spain,
Denmark, and Finland (2). The modelling studies consistently demonstrated both direct
(healthcare payer) and indirect (societal) cost-effectiveness of escitalopram over generic
citalopram, generic or branded fluoxetine, paroxetine, sertraline, and branded venlafaxine, with
greater efficacy, measured as remission over a 6-month treatment horizon (1). Sensitivity
analyses in these studies comparing escitalopram to fluoxetine, citalopram, paroxetine, and
venlafaxine demonstrated the robustness of the models, except for some sensitivity found when
the assumed remission rate for escitalopram was varied. The one prospective study the review
discussed found the difference in mean total healthcare costs over an eight-week period between
escitalopram and venlafaxine XR to be not significantly different (€110 vs. €161) (2). The mean
total cost from a societal perspective, both direct and indirect costs, were €765 for escitalopram
compared to €873 for venlafaxine XR.
Another review from 2007 (3) which aimed to look at cost-effectiveness of escitalopram
compared to citalopram, included seven studies from Finland, Norway, Austria, Belgium, and
the UK which all were reviewed in the first review discussed (1) except one study from Finland
(4). This review demonstrated lower direct costs (including costs of drugs, suicide, primary and
secondary care costs, ranging from approximately €35 to €504) and indirect costs (absenteeism,
46
ranging from approximately €25 to €1536) per successfully treated patient taking escitalopram
compared to those taking citalopram (3).
The third review from 2012, included 8 publications (3 prospective studies, including one (2)
from the Murdoch, et al. review (1) and 5 database analyses) with economic evaluations of
escitalopram compared to other antidepressants or placebo from the UK, USA, France, and
“multisite” (namely several European countries and some data from Canada) (5). The review
concluded that patients on escitalopram had lower total healthcare costs than venlafaxine,
duloxetine, and other SSRIs, and moreover, that escitalopram appeared more effective than
certain SSRIs and duloxetine with respect to treatment persistence, number of hospitalizations,
and some clinical symptom measures such as the Sheehan Disability Scale (SDS) and the
Montgomery-Asberg Depression Rating Scales-Self reported (MADRS-S). Compared to
venlafaxine, patients prescribed escitalopram in some of the included studies showed similar
therapeutic effectiveness but at a lower total healthcare cost (5). Of note, all three of the reviews
and all but one (6), which did not disclose funding sources, of the included studies in the reviews
disclosed conflicts of interest with Lundbeck and other pharmaceutical companies.
Database analyses Three of the 22 included articles were database analyses. One U.S. study compared escitalopram
(n=10465) to citalopram (n=4212) over 6-month periods between 2003 and 2005 from the
insurer’s perspective and found that the total healthcare costs from multivariate analyses were an
average of $1174 less in the escitalopram group (p<.001), and that the average total medical
services costs (-$972) and total prescription drug costs (-$170) were both significantly lower in
the escitalopram group (both P <.001) (7). The major depressive disorder (MDD)-related costs
(medical service and pharmacy costs related to a diagnosis of MDD) were on average $117 less
(P<0.001) per patient in the escitalopram group compared to citalopram. The authors
distinguished between the two on the grounds that MDD is often associated with multiple co-
morbidities, and that the presence of MDD may in fact worsen outcomes related to those co-
morbidities.
A Spanish study of 965 individuals followed for an 18-month period between 2003 and 2007
compared total (direct and indirect) cost-effectiveness of escitalopram to citalopram and
venlafaxine (8). In their uncorrected model (in which significant differences in remission rates,
age, sex, and various co-morbidities were not corrected for), total costs per patient per year were
significantly lower for escitalopram users (€2621.4) compared to citalopram (€3112.3) and
venlafaxine (€3715.5) with p values <0.05. When the model was adjusted for the aforementioned
differences, the results held: escitalopram users (€2276.20) as compared to citalopram
(€3093.80) and venlafaxine (€3801.20) with p values of 0.05. There was additionally a
significantly higher rate of remission in those on escitalopram (58%) compared to citalopram
(38.3%) at P=<0.001 but not significantly different from the venlafaxine group (32.4%). The
summary of these results implies dominance of escitalopram over citalopram and similar cost-
effectiveness compared to venlafaxine.
The final database analysis had a different outcome of paroxetine cost-effectiveness, pre and post
generic paroxetine introduction into the market, to fluoxetine, sertraline, citalopram, and
escitalopram. It too was a 6-month study of patients on these medications between 2001-2004
47
(n=5629 post-introduction). The results relevant to escitalopram found that generic but not brand
paroxetine dominated escitalopram on direct cost-effectiveness (9). This study declared no
conflicts of interest whereas the other two received funding from pharmaceutical companies
(Forest Laboratories and Lundbeck).
Modeling analyses The remaining seventeen publications were modelling studies with a decision-analytic approach,
largely from Europe (10–20) and the United States (21–23) but two from Singapore (24,25) and
one from Thailand (26). Study periods ranged from as short as 10 weeks (12) to as long as 2
years (19), though the vast majority were 6 months or 1 year. Most studies aimed to compare
cost-effectiveness of escitalopram to venlafaxine, duloxetine, and other SSRIs, though one study
compared agomelatine to escitalopram and other drugs (19). The primary outcomes of the studies
were 1) the effectiveness of the medication, generally measured as remission or meaningful
symptom reduction (usually by half) per symptom scales such as the MADRS or the Hamilton
Depression Rating Scale (HAM-D) and 2) the expected costs incurred, both from the direct and
indirect perspectives. All articles that studied escitalopram against other drugs assumed
escitalopram as the first-line treatment, except two (14,23), which looked at cost-effectiveness of
escitalopram as a second-line treatment. There was some heterogeneity to the steps used in the
decision models, such as variability in the number of lines of treatment (with a maximum of 4th
-
line treatment) and which medications were designated to each line. An overarching limitation to
the results is that all of the studies declared funding sources from or conflict of interests with
pharmaceutical companies that market the drug of study. Other limitations were generally
addressed by authors, the most concerning of which was populating the model with limited
comparative data between medications.
i. Escitalopram vs. venlafaxine The results of studies comparing escitalopram and venlafaxine were mixed. One study in
Belgium showed that while escitalopram dominated, meaning that efficacy achieved was higher
at a lower cost, venlafaxine from the societal perspective, it did not dominate from the insurer’s
perspective. The calculated incremental cost-effectiveness ratio (ICER) was €6352 per quality-
adjusted life year (QALY) (10). At a willingness-to-pay (WTP) threshold of = €30000, there was
a 61% probability that escitalopram is the optimal strategy over venlafaxine. A study of nine
regions within Italy (18) as well as Sardinia (16) found that escitalopram dominated venlafaxine,
but lost dominance when the remission rate of escitalopram was lowered by 5% (18). A Swedish
study found that escitalopram dominated venlafaxine from the insurer’s perspective but
calculated an ICER of €3732 per QALY from the societal perspective (20). All of these studies
modeled costs over a year-long period and did not adjust cost utilities for adverse events. A
Dutch study modeled costs over 26 weeks and modulated cost utilities to include medication-
related adverse events, finding a direct ICER of €16636 per QALY against venlafaxine but
domination with respect to indirect costs (11). With a 5% reduction in escitalopram remission
rates, the ICER rose to €39250. In Sweden, over a similar 6-month period and adjusting cost
utilities for adverse events, results were that €169.15 would be saved per patient treated with
escitalopram over venlafaxine (13). Sensitivity analyses demonstrated a 62.2% probability that
escitalopram would be the dominant treatment of 10,000 Monte Carlo patients. At a WTP of
€22080, this rose to 78.4% chance, and higher to 82.3% at a WTP of €33600. Meanwhile a
Danish study found that cost-effectiveness was similar between escitalopram and venlafaxine
48
(15). A Markov-analysis in Germany found similar results, calculating an ICER of €7446 in
primary care practices and €9836 in specialist care per successfully treated patient (12).
Venlafaxine costs per responder was found to be 34% and 42% higher than escitalopram costs
per responder in primary care and specialist care practices respectively. A Swedish study further
looked at using escitalopram as a second-line treatment and found it dominated both venlafaxine
and duloxetine from the indirect and direct cost perspectives (14). In the U.S., a study of second-
line treatments found that the ratio of cost per patient achieve remission for escitalopram was
$16,100, second to venlafaxine at $14,275 (23). Moving to Asia, a study in Singapore
determined a 68.1% treatment success rate for escitalopram at $2845 per patient as compared to
a lower (66%) success rate for venlafaxine at a higher cost of $3176 per patient (25). However,
another Singaporean study did not find that escitalopram clearly dominated any drug except
duloxetine and in fact was dominated by venlafaxine (24). The Thai study demonstrated that
1768 baht would be saved per patient treated with escitalopram over venlafaxine over the six-
month period (26). Overall, the cost-effectiveness of escitalopram as compared to venlafaxine is
likely quite similar, given the number of studies that did not find clear dominance between the
two, and variable robustness of modeling that did.
ii. Escitalopram vs. duloxetine In the one U.S. study comparing escitalopram to duloxetine, the Markov utility analysis
demonstrated clear dominance over duloxetine with a mean one-year direct cost of $903 with a
mean estimate efficacy of 41.0 quality-adjusted life weeks (QALW) for escitalopram as
compared to $1633 and 38.2 QALWs for duloxetine with no overlap in 95% confidence intervals
on either parameter (22). None of the 1000 simulations as part of sensitivity analyses changed
the model such that duloxetine was preferred. Nordstrom et al., and Khoo et al., out of Sweden
and Singapore respectively also found that escitalopram dominated duloxetine from both the
healthcare and societal perspectives (14,24).
iii. Escitalopram vs. other SSRIs Comparisons between escitalopram and other SSRIs were somewhat more robust. In nine
regions of Italy (94) as well as Sardinia (95) in Italy, escitalopram dominated venlafaxine XR,
sertraline, paroxetine, citalopram, fluoxetine, duloxetine, and fluvoxamine except in Sardinia
where the ICER against sertraline was found to be €2120.5 per QALY from the healthcare
perspective. On closer look in Lombardy (96), though it was included in the study encompassing
nine Italian regions (94), escitalopram dominated citalopram but had an ICER of €1080.0 against
paroxetine and €4395.0 against sertraline. The Dutch study found escitalopram dominated
citalopram from a societal perspective but calculated an ICER of €7553 per QALY from the
healthcare perspective (97). In Denmark, escitalopram dominated citalopram from both
perspectives; the total expected cost per successfully treated patient was lower for escitalopram
(DKK 22,323 healthcare perspective, DKK 72,399 societal perspective) than for citalopram
(DKK 25,778 healthcare perspective, DKK 87,786 societal perspective) (98). The UK’s NICE
guideline conducted its own pharmacoeconomic modeling study based on the results of Cipriani
et al. 2009 (25) and drug pricing data in the UK in 2008 and concluded that mirtazapine appears
to be the dominant option followed by escitalopram or sertraline. The ICERs of escitalopram
compared to sertraline were calculated to be £32,987 and £27,172 per QALY for moderate and
severe depression respectively, both of which are above the current cost-effectiveness threshold,
£20,000 per QALY (4). The final recommendation from the perspective of pharmacoeconomics
49
for escitalopram was third to mirtazapine and sertraline. A U.S. study found dominance over
sertraline with 88.5% probability that escitalopram dominates in 10,000 Monte Carlo simulations
(99). Looking at escitalopram as a second-line treatment, its cost-effectiveness ratio at $16,100
topped sertraline at $16,132, generic SSRIs at $16,714, and paroxetine CR at $18,121 per patient
achieving remission (100). The study then compared these brand medications to generic SSRIs
(fluoxetine, paroxetine, and citalopram), as that is what is usually used as second line treatment,
finding that the lowest ICER was $2073 for venlafaxine followed by escitalopram at $3566. In
Singapore, a 64.7% treatment success rate for escitalopram at $3133 per patient compared
favorably to 60% treatment success rate fluvoxamine at $3297 per patient (101). Savings of 2002
baht per patient treated with escitalopram instead of fluoxetine were found in a Thai modeling
study, though one major limitation with this study was that the remission rates in the model were
populated with data from head-to-head comparisons between escitalopram and citalopram, as
few publications existed at the time comparing escitalopram and fluoxetine (102). A Singaporean
decision-analysis over six months found that escitalopram dominated duloxetine and was
dominated by venlafaxine and mirtazapine but comparable to several other drugs including
fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone, and agomelatine (103). This study
represents the least favorable cost-effectiveness profile of all studies here.
iv Agomelatine vs. escitalopram Finally, one study from Greece was included that aimed to measure the cost-effectiveness of
agomelatine against SNRIs and SSRIs including escitalopram and generic escitalopram (19). In
terms of direct costs, the calculated ICER was €10591 per QALY against escitalopram and
€15799 against generic escitalopram. When both indirect and direct costs were taken into
consideration, agomelatine dominated escitalopram and the calculated ICER was €3303 for
generic escitalopram. Generic escitalopram dominated all other SNRIs and SSRIs in the study
from the total cost perspective.
SUMMARY There are several studies from highly developed countries that suggest that escitalopram, as
compared to other antidepressants, is a more cost-effective treatment for depression, or at the
very least, cost-equivalent, given how few studies found cost-superiority of other medications
over escitalopram. Moreover, the UK’s NICE guidelines support the assertion that escitalopram
“is better in terms of costs and benefits compared with some of the antidepressants,” and found
escitalopram or sertraline to be second choice to mirtazapine from a cost-effectiveness
perspective (4). The biggest limitation to the above data is that the vast majority of articles was
supported by pharmaceutical companies that manufacture escitalopram. This was somewhat
compensated for by sensitivity analyses, assuming the worst possible profile for escitalopram,
which still demonstrated some degree of superiority over other available agents. Given that the
patent on branded escitalopram in the U.S. expired in 2012, after many of these studies were
conducted, one would expect an even more favorable cost-effectiveness profile given current
availability of generic versions.
50
12. Regulatory status
Branded escitalopram was approved by the FDA in 2002 and became generic in 2012. It is
approved for acute and maintenance treatment of major depressive disorder in adults and
adolescents aged 12-17 and generalized anxiety disorder in adults only (1).
Escitalopram is a nationally authorized medicinal product in several member countries of the
European Medicines Agency (EMA) (2) as well as in Canada (3). Escitalopram was first
included in the Australian Register of Therapeutic Goods in 2003 and is currently listed for the
treatment of major depression, social anxiety disorder, generalized anxiety disorder, and
obsessive-compulsive disorder (4). It was approved in Japan in 2011 for the treatment of
depression (5). A revision of precautions was made in 2012 stating that patients with prolonged
QT was associated with administration of escitalopram (6).
References
1. Food & Drug Administration
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021323s047lbl.pdf
Last accessed: 11/5/18
2. European Medicines Agency
https://www.ema.europa.eu/documents/psusa/escitalopram-list-nationally-authorised-medicinal-
products-psusa/00001265/201612_en.pdf
Last accessed: 11/5/18
3. Health Canada
https://www.canada.ca/en/indigenous-services-canada/services/non-insured-health-benefits-first-
nations-inuit/benefits-services-under-non-insured-health-benefits-program/drugs-pharmacy-
benefits/drug-benefit-list/list-drug-prod.html
Last accessed: 11/5/18
4. Australian Government, Department of Health, Therapeutic Goods Administration
https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-
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5. Japanese Pharmaceuticals and Medical Devices Agency
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6. Japanese Pharmaceuticals and Medical Devices Agency
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Last accessed: 11/5/18
51
13. Pharmacopoeial standards
British Pharmacopoeia: No
European Pharmacopoeia: Yes
Indian Pharmacopoeia: Yes
International Pharmacopoeia: No
United States Pharmacopoeia: Yes
References
British Pharmacopoeia: http://www.pharmacopoeia.co.uk/
Last accessed Nov 5, 2018.
European Pharmacopoeia 9th Edition: http://www.edqm.eu/en/european-pharmacopoeia-publications-
1401.html
Last accessed Nov 5, 2018.
Indian Pharmacopoeia: http://ipc.nic.in/
Last accessed Nov 5, 2018.
International Pharmacopoeia:
http://www.who.int/medicines/publications/pharmacopoeia/overview/en/index.html
Last accessed Nov 5, 2018.
United States Pharmacopoeia: http://www.usp.org/
Last accessed Nov 5, 2018.
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APPENDIX Letters of Support
127 Yongmasan-ro,Gwangjin-g`u,
Seoul, Republic of Korea, 04933
T +82 2 2204 0114 F +82 2 2204 0387
www.ncmh.go.kr
62
Oct 8, 2018 The Secretary of Expert Committee on the Selection and Use of Essential Medicines Medicine Access and Rational Use (MAR) Department of Essential Medicines and Health Products (EMP) World Health Organization 20 Avenue Appia CH-1211 Geneva 27 Switzerland
Dear Secretariat, I am writing to you on behalf of the National Center for Mental Health in Korea and I would like to support the application being made by Dr. Iona Kiran Machado at the Stanford University to have escitalopram added to the WHO List of Essential Medicines (WHO EML). Currently, WHO essential medicines include only amitriptyline and fluoxetine for depressive disorders. The tricyclic antidepressants (TCAs) such as amitriptyline are less well-tolerated than many newer antidepressants including selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). Fluoxetine is the only SSRI listed in WHO essential medicines. However, differences in individual pharmacology, efficacy, and safety profiles among SSRIs should be taken into consideration to use an appropriate agent for a given patient. Escitalopram, the active S‐enantiomer of racemic citalopram, has been widely used in the treatment of patients with major depression and appears to give superior efficacy and tolerability from a clinical point of view with our many years of experience in medical practice. The efficacy and safety of escitalopram have been demonstrated by many studies. Escitalopram was significantly more efficacious as well as better tolerated than fluoxetine in meta-analysis conducted on new-generation antidepressants for the acute treatment of major depression in adults [1]. Furthermore, escitalopram was the best cost-effective treatment for depression when compared with many other SSRIs and SNRIs. The expected cost of treatment from escitalopram was cheaper and was associated with a larger health gain in terms of quality adjusted life years (QALYs) than that from fluoxetine [2, 3]. We believe that more than one SSRI should be considered as essential drugs. It is an important point that patients `may respond to specific SSRIs differently and it is difficult to predict which agent will be the most effective for each patient. Therefore, I would like to make a special appeal that escitalopram should be added to WHO essential medicines. Respectfully,
Tae-Yeon Hwang MD, PhD, MPH
127 Yongmasan-ro,Gwangjin-g`u,
Seoul, Republic of Korea, 04933
T +82 2 2204 0114 F +82 2 2204 0387
www.ncmh.go.kr
63
Director, Division of Mental Health Service and Planning, National Center for Mental Health (NCMH), Ministry of Health and Welfare, Seoul, Korea President, Korean Association of Social and Community Psychiatry References:
1. CIPRIANI, Andrea, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. The lancet, 2009, 373.9665: 746-758.
2. RAMSBERG, Joakim; ASSEBURG, Christian; HENRIKSSON, Martin. Effectiveness and cost-effectiveness of antidepressants in primary care: a multiple treatment comparison meta-analysis and cost-effectiveness model. PloS one, 2012, 7.8: e42003.
3. SULLIVAN, Patrick W., et al. A comparison of the direct costs and cost effectiveness of serotonin reuptake inhibitors and associated adverse drug reactions. CNS drugs, 2004, 18.13: 911-932.