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Escitalopram: A Review of its Use in the Management of Major

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 CNS Drugs 2003; 17 (5): 343-362
ADIS DRUG EVALUATION 1172-7047/03/0005-0343/$30.00/0

 Adis Data Information BV 2003. All rights reserved.

Escitalopram
A Review of its Use in the Management of Major
Depressive and Anxiety Disorders
John Waugh and Karen L. Goa
Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by:

F. Belpaire, School of Medicine, State University of Ghent, Ghent, Belgium; P. Blier, Department of
Psychiatry, University of Florida, Gainesville, Florida, USA; J. A. Kotzan, College of Pharmacy, University of
Georgia, Athens, Georgia, USA; Y.M. Lam, Department of Pharmacology, University of Texas Health Center,
San Antonio, Texas, USA; S. Seedat, Department of Psychiatry, Medical Research Council, Cape Town, South
Africa.

Data Selection
Sources: Medical literature published in any language since 1980 on escitalopram, identified using Medline and EMBASE, supplemented
by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published
articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search terms were ‘escitalopram’. EMBASE search terms were ‘escitalopram’. AdisBase search terms were
‘escitalopram’ or ‘S-citalopram’. Searches were last updated 10 March 2003.
Selection: Studies in patients who received escitalopram. Inclusion of studies was based mainly on the methods section of the trials. When
available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and
pharmacokinetic data are also included.
Index terms: escitalopram, anxiety, depression, panic disorder, pharmacodynamics, pharmacokinetics, therapeutic efficacy,
pharmacoeconomics, tolerability, dosage and administration, place in disease management.

Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
2. Pharmacodynamic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
2.1 Inhibition of Serotonin Reuptake and Receptor Selectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
2.2 Behavioural Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
3. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
3.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
3.2 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
3.3 Pharmacokinetics in Special Patient Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
3.4 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
4.1 Major Depressive Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
4.1.1 As Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
4.1.2 As Maintenance Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
4.2 Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
4.2.1 Generalised Anxiety Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
4.2.2 Social Anxiety Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
4.2.3 Panic Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
344 Waugh & Goa

5. Pharmacoeconomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
6. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
6.1 In Major Depressive Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
6.1.1 As Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
6.1.2 As Maintenance Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
6.2 In Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
7. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
8. Place of Escitalopram in the Management of Major Depressive and Anxiety Disorders . . . . . . . . . . 358
8.1 In Major Depressive Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
8.2 In Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
8.3 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360

Summary
Abstract Escitalopram is the therapeutically active S-enantiomer of RS-citalopram, a com-
monly prescribed SSRI. The R-enantiomer is essentially pharmacologically inac-
tive.
Escitalopram 10 or 20 mg/day produced significantly greater improvements in
standard measurements of antidepressant effect (Montgomery-Åsberg Depression
Rating Scale [MADRS], Clinical Global Impressions Improvement and Severity
scales [CGI-I and CGI-S] and Hamilton Rating Scale for Depression [HAM-D])
in patients with major depressive disorder (MDD) than placebo in several 8-week,
placebo-controlled, randomised, double-blind, multicentre studies. Symptom
improvement was rapid, with some parameters improving within 1–2 weeks of
starting escitalopram treatment. In addition, escitalopram showed earlier and
clearer separation from placebo than RS-citalopram, at one-quarter to half the
dosage, in 8-week, placebo-controlled trials; had significantly better efficacy than
RS-citalopram in a subgroup of patients with moderate MDD in a 24-week trial;
and produced sustained response and remission significantly faster than venlafax-
ine extended release in patients with MDD. Escitalopram reduced relapse rate
compared with placebo and increased the percentage of patients in remission in
long-term trials (up to 52 weeks).
Consistently significant improvements for all efficacy parameters were also
observed in patients with generalised anxiety disorder, social anxiety disorder and
panic disorder treated with escitalopram for 8–12 weeks in individual, random-
ised, placebo-controlled, double-blind investigations.
The good tolerability profile of escitalopram is predictable and similar to that
of RS-citalopram. Such adverse events as nausea, ejaculatory problems, diarrhoea
and insomnia are expected but, with the exception of ejaculatory problems and
nausea, which is mild and transient, these were generally no more frequent than
with placebo in fully published clinical trials. No adverse events not previously
seen in acute trials were reported with long-term use.
Conclusions: Escitalopram, the S-enantiomer of RS-citalopram, is a highly selec-
tive inhibitor for the serotonin transporter, ameliorates depressive symptoms in
patients with MDD at half the RS-citalopram dosage, has a rapid onset of
symptom improvement and has a predictable tolerability profile of generally mild
adverse events. Like RS-citalopram, escitalopram is expected to have a low
propensity for drug interactions, a potential benefit in the management of patients

 Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (5)
Escitalopram: A Review 345

with comorbidities. In combination, these properties place escitalopram, like other

SSRIs, as first-line therapy in patients with MDD. Escitalopram is indicated for
use in patients with panic disorder in Europe and, should further evidence confirm
early findings that escitalopram reduces anxiety, the drug may well find an
additional role in the management of anxiety disorders.
Pharmacodynamic Escitalopram is the therapeutically active S-enantiomer of RS-citalopram, which
Properties is a highly selective and effective serotonin reuptake inhibitor. The antidepressant
mechanism of escitalopram is presumed to be a result of stimulation of ser-
otonergic neurotransmission in the CNS as a consequence of higher serotonin
levels resulting from inhibition of the serotonin transporter.
Escitalopram has no or very low affinity for a variety of other serotonin,
dopamine, α- and β-adrenergic, histamine, muscarinic and benzodiazepine recep-
tors. It also does not bind to or has low affinity for a range of ion channels
including those for Na+, K+, Cl– and Ca2+.
In rat models predictive of antidepressant activity, escitalopram demonstrated
higher activity than RS-citalopram. The minimum effective dose was 4-fold lower
with escitalopram than with RS-citalopram in reducing aggressive behaviour in
the resident-intruder rat model and in reducing panic-like anxiety in rats after
electrical stimulation of the dorsal peri-aquaductal grey matter. A trial using a
conditioned fear model in rats found that escitalopram reversed suppression of
exploratory activity more rapidly than a comparable dose of S-citalopram in
RS-citalopram. This qualitative difference between S-citalopram and
RS-citalopram was confirmed by another in vivo trial that showed higher extracel-
lular serotonin concentrations in the frontal cortex of rats after injection with
escitalopram than in rats treated with a racemic mixture of S-citalopram and
R-citalopram, indicating inhibition of the S-enantiomer by the R-enantiomer in the
racemate.
Pharmacokinetic Escitalopram shows linear and dose-proportional pharmacokinetics with steady-
Properties -state plasma concentrations achieved in 1 week in healthy volunteers. The mean
steady-state area under the plasma concentration-time curve (0–24h) after a
dosage of 10 mg/day was 360.2 ng • h/mL in healthy volunteers.
After a single dose of escitalopram 20mg, peak plasma concentrations were
reached in 4–5 hours and were not affected by food intake. Absolute bioavailabili-
ty of RS-citalopram is about 80% and binding to human plasma proteins of
escitalopram is approximately 56%. The apparent volume of distribution of
escitalopram after oral administration is 12–26 L/kg. The pharmacokinetic profile
of the S-enantiomer is the same whether given as escitalopram 10mg or
RS-citalopram 20mg.
Escitalopram is transformed to two metabolites, S-demethylcitalopram and
S-didemethylcitalopram, both of which are much less potent than the parent drug.
Alternatively, the nitrogen atom may be oxidised to the N-oxide metabolite.
Escitalopram is the predominant plasma compound. The primary isoenzymes
involved in metabolising escitalopram are cytochrome P450 (CYP) 2C19,
CYP3A4 and CYP2D6.
Elimination of escitalopram is principally via hepatic and renal routes as
metabolites. Oral clearance of escitalopram is 36 L/h (600 mL/min) and the
elimination half-life (t1/2) is between 27 and 32 hours.

 Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (5)
346 Waugh & Goa

There are no sex-related differences in escitalopram pharmacokinetics; howev-

er, escitalopram is eliminated more slowly in the elderly but maximum plasma
concentration is unchanged thus increasing systemic exposure. In addition, oral
clearance of RS-citalopram was reduced by 37% and t1/2 doubled in patients with
hepatic impairment.

Therapeutic Efficacy
Antidepressive efficacy was observed in patients with major depressive disorder
(MDD) in 8-week trials with significant improvements in Montgomery-Åsberg
Depression Rating Scale (MADRS) scores in patients receiving escitalopram 10
or 20 mg/day versus those receiving placebo noted as early as 1–2 weeks after
starting therapy. Follow-on studies found that escitalopram reduced the long-term
risk of relapse and continued to reduce MADRS scores. Significant improvements
were also observed in all secondary efficacy parameters including the Hamilton
Rating Scale for Depression (HAM-D) and the Clinical Global Impressions
Improvement and Severity scales (CGI-I and CGI-S) scores, and at least half of
patients receiving escitalopram responded to treatment.
Escitalopram showed earlier and better efficacy than RS-citalopram in a
subgroup of patients with moderate MDD after 24 weeks and produced sustained
response and remission significantly more rapidly (p < 0.05) than venlafaxine
extended release (XR) at several timepoints over 8 weeks in patients with this
disorder. In addition, improvements in quality of life (QOL) were experienced in
the one study to report this.
Significantly greater reductions in Hamilton Rating Scale for Anxiety
(HAM-A) scores were observed in 124 patients, meeting the DSM-IV criteria for
generalised anxiety disorder (GAD), who received escitalopram than in 128
patients meeting the same criteria who received placebo for 8 weeks. Improve-
ments were also observed in several secondary efficacy parameters in the patients
receiving escitalopram.
In a 12-week study in patients who met the DSM-IV criteria for social anxiety
disorder (SAD), those receiving escitalopram (n = 181) showed greater reductions
in all SAD measurement scores and in disability scores than those receiving
placebo (n = 177). The primary efficacy parameter was changes in Liebowitz
Social Anxiety Scale scores from baseline to week 12. Secondary efficacy
parameters included CGI-I scores, changes in CGI-S scores and Sheehan Disabili-
ty scores over the same period.
Escitalopram was significantly more effective than placebo in the treatment of
panic disorder for all efficacy parameters in a 10-week trial. Efficacy measure-
ments included frequency of panic attacks, the Panic and Anticipatory Anxiety
Scale, Panic and Agoraphobia Scale, HAM-A, CGI-I and CGI-S scores, the
Patient Global Evaluation and a QOL questionnaire. Improvements were apparent
by week 4 in patients with GAD or panic disorder.

Pharmacoeconomics Two decision analytic studies carried out in Finland and Sweden found that, when
used to treat MDD, escitalopram was more cost effective than RS-citalopram,
fluoxetine or venlafaxine. In addition, the Finnish study found that cost utility
(cost per quality-adjusted life-year gained) was greater for escitalopram than for
the other three drugs.

 Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (5)
Escitalopram: A Review 347

Tolerability The adverse events profile for escitalopram is similar to that observed with
RS-citalopram in both MDD and anxiety disorders. Discontinuation rates due to
adverse events were similar in patients receiving escitalopram or placebo in
several trials.
Nausea and ejaculatory problems were reported in both fully published trials in
patients with MDD. In addition, diarrhoea, insomnia, dry mouth, headache and
upper respiratory tract infections were experienced by patients receiving escitalo-
pram, although the incidence of these events was not significantly higher than in
patients receiving placebo.
Fewer patients receiving escitalopram withdrew because of adverse events
than patients treated with venlafaxine XR.
A 52-week follow-on trial found no difference in the adverse events profile for
escitalopram than that observed in 8-week, double-blind studies.
The adverse events profile from three trials in patients with GAD, SAD or
panic disorder receiving escitalopram was similar to that observed in patients with
MDD. The withdrawal rate because of adverse events was low and similar to that
of placebo.
Dosage and The recommended dosage of escitalopram for the treatment of MDD is 10 mg/day
Administration which, depending on the individual patient response, may be titrated to a maxi-
mum dosage of 20 mg/day. In Europe, escitalopram is also approved for the
treatment of panic disorder; the recommended initial dosage is 5 mg/day for 1
week then titrated to 10 mg/day. The dosage may be further increased to 20 mg/
day, dependent on patient response to treatment. Administration is once daily in
the morning or evening and escitalopram may be taken with or without food.
In elderly patients or patients with hepatic impairment, the maximum recom-
mended dosage is 10 mg/day. In Europe, it is recommended that treatment be
initiated at 5 mg/day in these patients. No dosage adjustment is required in
patients with mild to moderate renal impairment; however, escitalopram should be
used with caution in patients with severe renal impairment.
Escitalopram is contraindicated in combination with irreversible monoamine
oxidase inhibitors (MAOIs) and a period of at least 2 weeks should be allowed
between discontinuation of escitalopram and commencement of an irreversible
MAOI and vice versa.

1. Introduction Direct and indirect costs of depression in the US

Depression is a common, debilitating and some-
times fatal disorder, which limits occupational and
social functioning and diminishes well-being and
quality of life (QOL).[1,2] It has a lifetime prevalence
rate of about 17%[2-4] and approximately two-thirds
of patients with depression are women.[5] In 70–80%
of cases it is a chronic recurring condition.[4-6] De-
pression represents a significant burden on global
healthcare resources[4] and is one of the most com-
mon reasons for attending a general practitioner.[7,8]
were estimated in 1990 at $US44 billion per an-
num.[2,9]
According to the neurotransmitter receptor hy-
pothesis, a factor in the aetiology of depression may
be dysfunction of the central serotonin 5-HT2 recep-
tor.[10] A variety of drugs have been developed with
the aim of regulating serotonin levels in the brain in
order to treat affective disorders.[11] SSRIs are the
first drugs developed for this purpose based on
molecular targeting and have proved useful in the

 Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (5)
348
NC
O O
CH2CH2CH2NMe 2
F F
Escitalopram
Fig. 1. Molecular structure of escitalopram (the generic designation given to S-citalopram) and R-citalopram.
management of major depressive disorder (MDD)
as well as anxiety disorders.[11,12] They bind to the
serotonin transporter protein, inhibiting transport
(uptake) of serotonin into serotonergic neurons. This
results in increases in availability of serotonin to the
synapses and ultimately in an increased serotonergic
function within the CNS.[13] SSRIs share similar
efficacy to other antidepressants but have more be-
nign tolerability profiles and low toxicity in over-
dose.[14] They are currently considered first-line
treatment for MDD.[7,12,14-16]
In addition to MDD, SSRIs are first-line treat-
ment for other indications including the anxiety
disorders.[10,14,17] The pathogenesis of anxiety disor-
ders is obscure, but the efficacy of SSRIs in the
treatment of anxiety suggests that an abnormal ser-
otonergic function may be involved.[10]
RS-citalopram is a commonly prescribed SSRI. It
is a racemic drug that is structurally distinct from
other SSRIs with an active S-enantiomer and an
essentially pharmacologically inactive R-enanti-
omer.[10,18,19] Escitalopram, the active S-enantiomer,
is now approved for use in the US for treatment of
MDD[20] and in Europe for MDD and panic disor-
der.[21] Escitalopram and its use in the treatment of
MDD and the anxiety disorders is the subject of this
evaluation.
2. Pharmacodynamic Profile
Escitalopram is the S-enantiomer of RS-citalo-
pram, which acts as an SSRI.[13,20,22] Its chemical
structure differs from that of any other SSRI (figure
1). The antidepressant mechanism of escitalopram,
like that of RS-citalopram,[23] is presumed to be a
 Adis Data Information BV 2003. All rights reserved.
Waugh & Goa
CN
Me 2 NCH2CH2CH2
R-citalopram
result of stimulation of serotonergic neurotransmis-
sion in the CNS.[10,23]
2.1 Inhibition of Serotonin Reuptake and
Receptor Selectivity
Escitalopram is a highly selective and potent
ligand for the serotonin transporter.[13,24] In rat brain
synaptosomes, escitalopram was approximately
twice as potent as RS-citalopram (concentration in-
hibiting 50% of effect [IC50] = 2.1 vs 3.9 nmol/
L).[25] Escitalopram had a binding affinity constant
(Ki) of 1.1 nmol/L (vs 1.6 nmol/L for RS-citalo-
pram) at human serotonin transporters in vitro.[13]
Escitalopram was the most selective inhibitor of all
SSRIs tested in the above study; the Ki for serotonin
uptake was 5900 times lower than for noradrenaline
(norepinephrine) uptake.[13] Escitalopram has at
least 100-fold greater selectivity for serotonin
reuptake sites than for other sites in vitro; thus, it has
no or very low affinity for 5-HT1-7, dopamine D1-5,
α- and β-adrenergic, histamine H1-3, muscarinic1-5
and benzodiazepine receptors.[20] It also does not
bind to, or has low affinity for, various ion channels
including Na+, K+, Cl– and Ca2+ channels.[13,20] The
potency of escitalopram is at least 30–100 times that
of the R-enantiomer, both in the in vitro inhibition of
serotonin reuptake and the in vivo inhibition of
serotonin neuronal firing rate in the dorsal raphe
nucleus.[19,20,24-27] Serotonin levels in the frontal cor-
tex of freely moving rats were increased from base-
line by approximately 4-fold 20 minutes after ad-
ministration of a single subcutaneous injection of
escitalopram 2.0 mg/kg. This was significantly
greater than the approximately 2-fold increase ob-
served in rats given RS-citalopram 4.0 mg/kg (p <
CNS Drugs 2003; 17 (5)
Escitalopram: A Review
0.05).[28] No change in serotonin levels was ob-
served with R-citalopram 2.0 mg/kg.[28] Interesting-
ly, when R-citalopram was infused into the frontal
cortex of rats 100 minutes prior to escitalopram
infusion, the effect of escitalopram on serotonin
levels was attenuated (p < 0.05); the mechanism for
this interference is as yet not known.[28]
2.2 Behavioural Studies
In rat models predictive of antidepressant activi-
ty, escitalopram demonstrated higher activity than
RS-citalopram.[27] The minimum effective dose was
4-fold lower with escitalopram than with RS-citalo-
pram against aggressive behaviour in a resident-
intruder rat model (0.25 vs 1 mg/kg)[27] and in
reducing panic-like anxiety in rats after electrical
stimulation of the dorsal peri-aquaductal grey matter
(1 vs 4mg base/kg).[29] A trial using a conditioned
fear protocol in rats found that escitalopram re-
versed the conditioned fear-induced suppression of
exploratory activity dose dependently and to a
greater extent than RS-citalopram at double the dose
(p < 0.01).[30]
3. Pharmacokinetic Profile
A single oral dose of escitalopram 20mg was
bioequivalent to a dose of RS-citalopram 40mg in a
study in 24 healthy men.[31] Data relating to the
pharmacokinetic characteristics of escitalopram
have been gathered from trials using this drug,[10,31]
Table I. The steady-state pharmacokinetic parameters of escitalopram (ESC) and its S-demethylcitalopram metabolite (S-DCT) following
multiple-dose administration of escitalopram 10 and 30 mg/day in healthy volunteers[31]
Pharmacokinetic Treatment regimen
parameter ESC 10 mg/day (n = 17)
ESC
Cmax (ng/mL) 20.6
tmax (h) 3.9
AUC0–24h (ng • h/mL) 360.2
t1/2 (h) 29.0
CL/F (L/h) 34.9
Vz/F (L) 1254.7
AUC0–24h = area under the plasma concentration-time curve from time 0 to time 24 hours; CL/F = apparent total body clearance; Cmax =
maximum plasma concentration; t1/2 = plasma elimination half-life; tmax = time to Cmax; Vz/F = apparent volume of distribution.
 Adis Data Information BV 2003. All rights reserved.
349
by extrapolating data obtained for RS-citalo-
pram[10,32] and from the manufacturer’s prescribing
information.[20,21]
3.1 Absorption and Distribution
RS-citalopram is a lipophilic compound that is
readily absorbed from the gastrointestinal tract after
oral administration.[10] It crosses the blood-brain
barrier via a non-stereoselective, bidirectional and
symmetrical carrier-mediated mechanism that is in-
dependent of active efflux mechanisms or monoam-
ine oxidases.[33] After a single 20mg dose of escita-
lopram, the time to peak plasma concentration
(Cmax) was 4–5 hours and was not affected by food
intake.[20] Absolute bioavailability of RS-citalopram
is approximately 80% and binding of escitalopram
to human plasma proteins is in the region of
56%.[10,20,21] Apparent volume of distribution after
oral administration of RS-citalopram is 12–26 L/
kg.[21]
The single- and multiple-dose pharmacokinetic
profile of escitalopram 10–30 mg/day is linear and
dose proportional (table I),[20,31] with steady-state
plasma concentrations being achieved in about 1
week in healthy volunteers receiving 10 mg/day.[20]
The pharmacokinetic profile, including the area
under the plasma concentration-time curve from
time 0 to 24 hours (AUC0–24h), of the S-enantiomer
are the same whether given as escitalopram 20mg or
as RS-citalopram 40mg.[31]
ESC 30 mg/day (n = 16)
S-DCT ESC S-DCT
7.4 64.4 19.4
7.5 4.1 6.0
152.0 1100.9 396.3
50.2 32.5 54.1
37.8
1461.0
CNS Drugs 2003; 17 (5)
350
3.2 Metabolism and Elimination
Escitalopram is metabolised in the liver to S-
demethylcitalopram (S-DCT), S-didemethylcitalo-
pram (S-DDCT) and to a lesser degree to an N-oxide
metabolite; however, in humans escitalopram is the
predominant plasma compound.[20,21] After multiple
doses, S-DCT is present at about 33% (table I) and
S-DDCT <5% of the concentration of the parent
drug.[20,21] Escitalopram is 7 and 27 times more
potent than S-DCT and S-DDCT in serotonin
reuptake inhibition, respectively, indicating that the
metabolites do not contribute significantly to the
antidepressant effects of escitalopram.[20]
In vitro studies have identified that the primary
isozymes involved in the N-demethylation of escita-
lopram and their contributions to net intrinsic clear-
ance are cytochrome P450 (CYP) 2C19 (37%),
CYP3A4 (35%) and CYP2D6 (28%).[26,34-36] Poor
metabolisers of CYP2C19 who received RS-citalo-
pram had significantly higher steady-state plasma
concentrations and AUCs than extensive metabolis-
ers (298 nmol/L vs 145 nmol/L and 8148 nmol • h/L
vs 4588 nmol • h/L; p ≤ 0.0005).[37]
Elimination of escitalopram and its metabolites is
assumed to be both hepatic and renal, with the major
part being excreted renally as metabolites.[21] Fol-
lowing oral administration, 8% of a dose of escitalo-
pram was recovered in the urine as parent drug and
10% as S-DCT.[20] Oral clearance of escitalopram is
36 L/h (600 mL/min).[20,21] The elimination half-life
(t1/2) is in the range of 27–32 hours for escitalo-
pram.[20]
3.3 Pharmacokinetics in Special
Patient Groups
There is no difference in mean AUC, Cmax or t1/2
for escitalopram between men and women and no
sex-related dosage adjustments are required;[20,21]
however, while Cmax is unchanged, escitalopram is
eliminated more slowly in the elderly than in young-
er patients, thus increasing systemic exposure
(AUC) by about 50%.[20] Oral clearance of RS-
citalopram was reduced by 37% and t1/2 doubled in
 Adis Data Information BV 2003. All rights reserved.
Waugh & Goa
patients with hepatic impairment. Accordingly, dos-
age adjustments are recommended in both these
groups of patients (section 7).[20,21]
No significant difference in all pharmacokinetic
parameters was observed between 12 healthy
paediatric volunteers (age range 10–17 years) and
11 healthy adult volunteers (age range 18–45 years)
who received RS-citalopram 20 mg/day for 1 week
followed by RS-citalopram 40 mg/day for 3 weeks
in a multicentre, open-label trial.[31]
No dosage adjustment is required in patients with
mild to moderate renal impairment based on data for
RS-citalopram showing a slight decrease of 17% in
oral clearance; however, no pharmacokinetic data
are available for patients with severe renal impair-
ment (creatinine clearance <1.2 L/h; <20 mL/
min).[20]
3.4 Drug Interactions
Data derived from in vitro enzyme inhibition
assays suggest that escitalopram has no inhibitory
effect on CYP3A4, CYP1A2, CYP2C9, CYP2C19
or CYP2E1.[20] Little inhibition is expected in in
vivo metabolism mediated by these cytochromes,
though data are limited.[20] Results of drug interac-
tion trials using RS-citalopram showed no CYP3A4,
and modest CYP2D6 inhibition.[20,38]
Coadministration of RS-citalopram with digoxin,
triazolam or ritonavir, a CYP3A4 inhibitor, did not
affect the pharmacokinetics of either RS-citalopram
or the other drug.[20]
Despite in vitro and in vivo studies suggesting
little or no inhibition of CYP2D6 by escitalopram,
coadministration of escitalopram 20 mg/day for 21
days with the tricyclic antidepressant desipramine, a
substrate of CYP2D6, resulted in a 40% increase in
Cmax and a 100% increase in AUC for desipramine.
The clinical significance of these findings is un-
known; however, caution is advised in the coadmin-
istration of CYP2D6 metabolisers and escitalopram.
Similar results were observed in the coadministra-
tion of escitalopram and metoprolol (Cmax for
metoprolol increased by 50% and AUC by 82%).[20]
CNS Drugs 2003; 17 (5)
Escitalopram: A Review 351

Treatment week
4. Therapeutic Efficacy
0 2 4 6 8
0
The therapeutic efficacy of escitalopram in pa-
tients with MDD in both specialist settings and −2

Change from baseline MADRS score

general practice (table II), has been investigated in
several placebo-controlled studies[39-42] as well as in
long-term and extension studies.[43,44] One study al-
so contained an RS-citalopram treatment arm[39] and
two were direct comparisons between escitalopram
and RS-citalopram or venlafaxine extended release
(XR).[45,46] In addition, its efficacy has been investi-
gated in the treatment of patients with generalised
anxiety disorder (GAD),[39,47] social anxiety disorder
(SAD)[48] and panic disorder.[49] Some of these stud-
ies are only evaluable as abstracts[41-45,47-49] and/or
posters.[43,44,46-49]
For MDD, each study was a randomised, double-
blind, multicentre trial in patients aged between 18
and 65 years who fulfilled the DSM-IV criteria for
MDD.[39-41,46] All studies were 8 weeks in length
except for a 24-week comparison with RS-citalo-
pram.[46] The primary efficacy parameter in all trials
was change in the Montgomery-Åsberg Depression
Rating Scale (MADRS) score from baseline.[39-41]
Three studies also employed the Clinical Global
Impressions Improvement and/or Severity scales
(CGI-I and CGI-S) as a secondary measure of de-
pression[39,40,46] and all studies utilised a measure of
response defined as a reduction in MADRS score by
≥50% from baseline during the course of the tri-
al.[39-42]
Patients had MADRS scores of ≥22 and ≤40 at
baseline in each study.[39-42] In two trials, patients
entered a 1-week, single-blind, placebo lead-in
period prior to randomisation into the double-blind
study.[39,40]
4.1 Major Depressive Disorder
4.1.1 As Treatment
Escitalopram 10 or 20 mg/day showed similar
efficacy to RS-citalopram 40 mg/day[39] and was
more effective than placebo[39,40,42] after 8 weeks’
treatment (table II). A pooled analysis, including a
total of 1321 patients with MDD (figure 2), showed
a significantly more rapid onset of action for escita-
−4
−6 *
†
−8
*
−10 LOCF
−12
** ** *
−14 **
** **
−16 PLA
**
†
CIT
−18 ESC
Fig. 2. Mean change from baseline in Montgomery-Åsberg Depres-
sion Rating Scale (MADRS) scores. Results of a pooled analysis of
three double-blind, multicentre trials in which patients with major
depressive disorder were randomised to treatment with escitalo-
pram (ESC) 10–20 mg/day, RS-citalopram (CIT) 20–40 mg/day or
placebo (PLA). Values are for observed cases, also given are last
observation carried forward (LOCF) adjusted figures for week 8
(reproduced from Gorman et al.,[50] with permission). * p < 0.05,** p
< 0.001 vs PLA; † p < 0.05, ESC vs CIT.
lopram than for RS-citalopram at week 1 (4.7 vs 3.7
reduction in MADRS score; p < 0.05).[50] This ana-
lysis also showed a significant difference in reduc-
tion of MADRS score between escitalopram and RS-
citalopram at week 8 in observed cases (–15 vs –14;
p < 0.05); however, this difference was not signifi-
cant using last observation carried forward (LOCF)
analysis.[50]
Reductions in MADRS scores, the primary end-
point, were greater with escitalopram than with pla-
cebo as early as week 1 (p < 0.05)[42] or 2 (p <
0.01)[39,40] and were maintained throughout treat-
ment.[39-42] Escitalopram decreased all MADRS sin-
gle-item scores further than placebo (p < 0.05) ex-
cept reduced appetite and lassitude in a trial using
LOCF analysis.[40]
Changes in CGI-I and CGI-S scores were report-
ed in some trials[39,40] and support the MADRS score
findings (table II). Escitalopram produced signifi-
cantly lower CGI-I scores from week 1 and CGI-S
scores from week 3 than placebo in one trial (p <
0.05) and this continued throughout treatment.[40]

 Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (5)
352 Waugh & Goa

Table II. Efficacy of escitalopram (ESC) versus placebo (PLA) or RS-citalopram (CIT) in patients with major depressive disorder. All studies
were 8-week, randomised, double-blind and multicentre in design unless otherwise stated
Reference No. of Treatment Changes in MADRS score Changes in CGI-I/CGI-S score Response
evaluable (mg/day) baseline wk4 wk8 baseline wk4 wk8 rate (%)a
patients
Burke et al.[39] 118b ESC 10 28.0 –11c –12.8** –/4.2 2.7c/3.2d 2.5**/2.9**e 50**
123b ESC 20 29.0 –11c –13.9** –/4.3 2.6c/3.3d 2.4**/2.9**e 51**
125b CIT 40 29.0 –10c –12* –/4.3 2.8c/3.4d 2.6*/3.1*e 46**
119b PLA 30.0 –7c –9.4 –/4.2 3.0c/3.5d 3.0/3.4e 28
Colonna et al.[46]f 165i ESC 10 29.5d Wk24: –21.6 Wk24: NA/
–2.5†g
174i CIT 20 30.2d Wk24: –20.6c Wk24: NA/–2.3g
Montgomery et al.[41]h 155id ESC 10–20 29.0 –11.3** –15d 63.7*d
and Lepola et al.[42]h
160id CIT 29.2d –13.6d 52.6d
154id PLA 28.7d –8.7 –12.1d 47.8d
Wade et al.[40] 191i ESC 10 29.0 –14.3** –16.3**j –/4.4 2.2*/3.1* 2.3**j/2.7* 55**
189i PLA 29.0 –11.6 –13.6j –/4.4 2.5/3.4 2.6/3 42
a Defined as >50% reduction in MADRS score.
b Outpatients treated in specialist settings.
c Estimated from graph.
d Data on file.[51]
e Mean scores.
f Poster.
g Change from baseline.
h Abstract.
i Primary care patients.
j Last observation carried forward.
CGI-I = Clinical Global Impressions Improvement scale; CGI-S = Clinical Global Impressions Severity scale; MADRS = Montgomery-Åsberg
Depression Rating Scale; NA = not applicable; * p ≤ 0.05, ** p < 0.01 vs PLA; † p < 0.05 vs CIT.

Both CGI-I and CGI-S scores were significantly
lower in patients who received escitalopram (p <
0.01) and RS-citalopram (p ≤ 0.05) than in patients
who received placebo at week 8 in another trial.[39]
At least half of patients who received escitalo-
pram responded to treatment (50–63.7%).[39-42] This
rate was significantly higher than with placebo
(28–47.8%; p < 0.05)[39,40,42] [table II], as was the
rate of remission (defined as patients achieving a
MADRS score of ≤12) in one trial (47% vs 34%; p <
0.01).[40] In addition, sustained response and remis-
sion were achieved 4.6 (p < 0.05) and 6.6 (p < 0.001)
days faster with escitalopram (mean dosage 12.1
mg/day) than with venlafaxine XR (mean dosage
95.2 mg/day at week 8) in a trial in 293 patients
treated in a primary care setting.[45] This trial also
reported escitalopram to be at least as effective as
venlafaxine XR as shown by MADRS (the primary
endpoint), CGI-I and HAM-D scores.[45]
Both escitalopram 10 and 20 mg/day were more
effective than placebo and as effective as RS-citalo-
pram 40 mg/day in alleviating depression (table
II).[39] In light of this result, the lower escitalopram
dosage was compared with RS-citalopram 20 mg/
day in a 24-week trial.[46] Results are available at
present only in poster form; however, escitalopram
10 mg/day was reported to have similar efficacy to
RS-citalopram in the total population (table II) but
greater efficacy in a subgroup of moderately de-
pressed patients (about half the population).[46]
MADRS scores were lower at week 24 (6 vs 8.4; p <
0.05) and the time to remission (≥50% of patients
with a MADRS score ≤12) was more rapid in the
escitalopram 10 mg/day than the RS-citalopram 20

 Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (5)
Escitalopram: A Review 353

Table III. Efficacy of escitalopram (ESC) as maintenance therapy in two long-term trials in patients with depression
Reference No. of Treatment Duration Change in MADRS score Change in HAM-D or CGI-S score Cumulative
evaluable (mg/day) (wk) baseline study end baseline study end relapse rate
patients (%)a
Rapaport et al.[43]b 93 ESC 10 or 20 36 7.2 –1.4* 7.7c –1.6*c 26**
32 PLA 36 6.2 0.7 6.6c –0.8c 40
Wade et al.[44]d 437 ESC 10 or 20 52 14.2 –8.4 2.7e –1.1e NAf
a Relapse defined as MADRS score >22 or discontinuation because of insufficient response.
b Randomised double-blind trial available as a poster.
c HAM-D data.
d Poster and abstract.
e CGI-S data.
f 86% of patients were in remission (MADRS score <12) at study end.
CGI-S = Clinical Global Impressions Severity scale; HAM-D = Hamilton Rating Scale for Depression; MADRS = Montgomery-Åsberg
Depression Rating Scale; NA = not applicable; PLA = placebo; * p < 0.05, ** p = 0.013 vs PLA.

mg/day group in this subgroup of patients (median
5.5 vs 7.3 weeks; no p value given).
In the only study to report QOL results,[39] escita-
lopram 10 and 20 mg/day improved QOL more than
placebo, as assessed by two patient-rated question-
naires: the Quality of Life Questionnaire (a 16-item
instrument) [difference in change from baseline in
score of 2.4 for the 10 mg/day group vs placebo; p =
0.04 and 4.8 for the 20 mg/day group vs placebo; p <
0.01] and the Center for Epidemiological Studies-
Depression Scale (difference in change from base-
line in score of –2.7 for the 10 mg/day group vs
placebo [p = 0.02] and –6.8 for the 20 mg/day group
vs placebo [p < 0.01]).
4.1.2 As Maintenance Therapy
Escitalopram reduces relapse, as shown in a
36-week, randomised, placebo-controlled, double-
blind trial in 274 patients[43] and patients showed
continued improvement in a 52-week, open-label
safety extension study in 588 patients[44] (table III).
Both studies followed on from initial 8-week, doub-
le-blind, randomised studies in which patients re-
ceived escitalopram, RS-citalopram or placebo. The
36-week trial was preceded by an 8-week flexible-
dose phase; during this phase all patients previously
given escitalopram, RS-citalopram or placebo re-
ceived escitalopram 10 or 20mg. Responders
(MADRS scores <12) then entered the double-blind
trial and received escitalopram 10 or 20mg or place-
bo (2 : 1 ratio).[43] Of the 274 patients enrolled, 125
patients were evaluable. Escitalopram decreased the
risk of relapse (the primary endpoint) by 44% com-
pared with placebo and produced significantly lower
MADRS and HAM-D scores (table III).[43] Fewer
patients treated with escitalopram than placebo met
DSM-IV-defined criteria for a major depressive epi-
sode (23% vs 35%; p = 0.03). Furthermore, in the
52-week study[44] the percentage of patients in re-
mission increased from 46% at baseline to 86% at
study end, and 60% of patients had achieved remis-
sion by week 4. MADRS and CGI-S scores de-
creased during the course of the study (table III),
indicating continuing improvement in depressive
symptoms, although no p-values versus baseline
were reported.[44]
4.2 Anxiety Disorders
4.2.1 Generalised Anxiety Disorder
Significantly greater reductions in Hamilton Rat-
ing Scale for Anxiety (HAM-A) scores were ob-
served at week 8 in patients randomised to receive
escitalopram 10 mg/day (titrating to 20 mg/day after
4 weeks if required) than in those receiving placebo
(p < 0.05).[47] In this multicentre, double-blind trial,
252 patients meeting the DSM-IV criteria for GAD
with a HAM-A score of ≥18 received escitalopram
10 mg/day (n = 124) or placebo (n = 128).[47] The
primary efficacy parameter was change from base-
line in HAM-A score. Secondary efficacy parame-
ters included a HAM-A psychic anxiety subscale,

 Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (5)
354 Waugh & Goa

Table IV. Efficacy of escitalopram (ESC) in the treatment of patients with generalised anxiety disorder. Reductions in scores from baseline
in different scales used to measure the severity of generalised anxiety are presented from an 8-week, double-blind, multicentre trial
available as a poster and abstract in which patients were randomised to receive ESC 10 or 20 mg/day (n = 124) or placebo (PLA) [n =
128][47]
Test Treatment group Baseline Wk4 Wk8
HAM-A ESC 22.8 –8.4*a –9.6*a
PLA 22.1 –6.3a –7.7a
HAM-A psychic anxiety subscale ESC 13.1 –4.6* –5.3**a
PLA 13.1 –3.2a –4.0
CGI-S ESC 4.3 –0.9** –1.2*
PLA 4.2 –0.6 –0.9a
HAD anxiety subscale ESC 12.7 a –3.0* –3.8**
PLA 12.9a –1.3 –2.3
a Data on file.[51]
CGI-S = Clinical Global Impression Severity scale; HAD = Hospital Anxiety and Depression scale; HAM-A = Hamilton Rating Scale for
Anxiety; * p < 0.05, ** p < 0.01 vs PLA.

Hospital Anxiety and Depression (HAD) anxiety
subscale, CGI-S and a patient-rated QOL scale.[47]
By week 4, patients receiving escitalopram regis-
tered significantly greater improvement in scores for
all efficacy parameters than those receiving placebo
and this was maintained to week 8 (table IV).[47]
There were significant improvements in QOL scores
from baseline to endpoint for patients who received
escitalopram versus those who received placebo (p <
0.05).[47] Items assessed included overall life satis-
faction and contentment, ability to function in daily
life, mood and overall sense of well-being.[47]
Additional support for an anxiolytic effect of
escitalopram is available from an 8-week trial in 491
patients with MDD randomised to escitalopram 10
or 20 mg/day, RS-citalopram 40 mg/day or placebo
(section 4.1.1).[39] Escitalopram significantly re-
duced anxiety symptoms, as measured by HAM-A
as a secondary efficacy parameter.[39] The difference
in mean change from baseline for escitalopram 10
and 20 mg/day was –1.1 (p = 0.04) and –2.6 (p <
0.01) versus placebo.[39]
4.2.2 Social Anxiety Disorder
A trial in 358 patients with a primary diagnosis of
SAD, according to DSM-IV criteria, found that pa-
tients who received escitalopram showed greater
reductions in SAD measurement scores than pa-
tients who received placebo.[48] After a 1-week, sin-
gle-blind placebo run-in period, patients were ran-
domised to a 12-week double-blind treatment period
with escitalopram 10 mg/day (which could be in-
creased to 20 mg/day after 4, 6 or 8 weeks) or
placebo.[48] The primary efficacy parameter was
changes to Liebowitz Social Anxiety Scale (LSAS)
scores from baseline to week 12. Secondary efficacy
parameters included changes in CGI-I, CGI-S and
Sheehan Disability Scale (SDS) scores over the
same period.[48] Patients were outpatients aged
18–65 years with a baseline LSAS score of ≥70 and
a CGI-S score of ≥4.[48]
Patients receiving escitalopram (mean dosage
14.7 mg/day) showed greater improvement in LSAS
parameters than those receiving placebo (figure
3).[48] In addition, mean CGI-I scores at week 12
were significantly better for patients who received
escitalopram than for patients who received placebo
(2.5 vs 2.9; p ≤ 0.01) as were mean changes from
baseline in CGI-S and SDS work and social life
scores (figure 4).[48]
4.2.3 Panic Disorder
Escitalopram was significantly more effective in
the treatment of panic disorder than placebo in a
10-week, randomised, double-blind trial in 351 pa-
tients with DSM-IV-defined panic disorder who had
experienced at least four panic attacks in the 4 weeks
prior to screening.[49] Patients had a baseline HAM-
D score ≤17 and were randomised to a starting
dosage of escitalopram 5 mg/day (increasing to 10
or 20 mg/day), RS-citalopram 10 mg/day (rising to
20 or 40 mg/day) or placebo, following a 2-week,

 Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (5)
Escitalopram: A Review 355

LSAS LSAS
LSAS fear/anxiety avoidance to placebo, including QOL and PGE scores (table
total score subscale subscale V).
0
Change in score from baseline

−5
−10
−15
−20
***
−25
−30
−35
**
−40
Fig. 3. Efficacy of escitalopram (ESC) in the treatment of social
anxiety disorder (SAD). Mean changes in Liebowitz Social Anxiety
Scale (LSAS) scores at study end for patients with SAD random-
ised to receive ESC 10 or 20 mg/day (n = 181) or placebo (PLA) [n
= 177] in a 12-week, multicentre, double-blind, flexible-dose
study.[48] * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001 vs PLA.
single-blind, placebo lead-in period.[49] Efficacy
measurements included panic attack frequency, the
Panic and Anticipatory Anxiety Scale, Panic and
Agoraphobia Scale, HAM-A, CGI-I and CGI-S
scores, the Patient Global Evaluation (PGE) and a
QOL questionnaire. Efficacy results were LOCF
adjusted.[49]
5. Pharmacoeconomics
Pharmacoeconomic studies in Finland[52] and
Sweden,[53] using a two-path decision analytic
*
model, found that escitalopram was more cost effec-
tive than RS-citalopram, fluoxetine (branded and
generic) or venlafaxine in the treatment of MDD
(table VI).[52,53] In addition, the Finnish study found
PLA wk12
that cost utility, expressed as cost per quality-adjust-
ESC wk12
ed life-year (QALY) gained was lower for escitalo-
pram than for the other three drugs (table VI).[52]
Successful treatment was defined as the number of
patients in remission (MADRS score ≤12) 6 months
after the start of treatment and was predicted based
on comparative trial data and published literature.
The model used combined success rates with ex-
pected 6-month total cost (including medical re-
source use [drug cost, physician service, general
practitioner outpatient, psychiatrist visit, hospital-
isation] as well as nonmedical costs [sickness ab-
sence, suicide, suicide attempt]) to arrive at the cost-
effectiveness ratios.[52,53]

Escitalopram produced significant reductions (p 6. Tolerability

≤ 0.05) in all assessments of panic disorder relative
Discontinuations due to adverse events were sim-
SDS SDS ilar in patients treated with escitalopram and placebo
CGI-S SDS work social life home life
0.0 in several large, well designed trials.[39,42,48,49,54,55]
Adverse events were generally mild and tran-
−0.5 sient.[39,40,42,48,49,54] Escitalopram thus shows a
Change from baseline

broadly similar tolerability profile to that of RS-

−1.0
citalopram.
−1.5 **
6.1 In Major Depressive Disorder
−2.0
6.1.1 As Treatment
−2.5 Nausea and ejaculatory problems were reported
** PLA wk12
−3.0
* in patients receiving escitalopram 10 or 20 mg/day
ESC wk12
Fig. 4. Efficacy of escitalopram (ESC) in the treatment of social
in both fully published, 8-week trials (see section
anxiety disorder (SAD). Mean changes from baseline in Clinical 4.1.1 for study details);[39,40] however, significance
Global Impressions Severity scale (CGI-S) and Sheehan Disability was not reported except for nausea (p < 0.05 vs
Scale (SDS) scores at study end for patients with SAD randomised
to receive ESC 10 or 20 mg/day (n = 181) or placebo (PLA) [n =
placebo) in one trial.[40] In addition, diarrhoea, in-
177] in a 12-week, multicentre, double-blind, flexible-dose study.[48] somnia and dry mouth were experienced by patients
* p ≤ 0.05, ** p ≤ 0.01 vs PLA. receiving escitalopram in one trial (figure 5),[39] and

 Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (5)
356 Waugh & Goa

Table V. Efficacy of escitalopram (ESC) in the treatment of panic disorder. Results of a 10-week, randomised, double-blind trial investigat-
ing the efficacy of ESC 5–20 mg/day, RS-citalopram (CIT) 10 mg/day (rising to 20 or 40 mg/day) or placebo (PLA) in the treatment of panic
disorder. Results are expressed as changes from baseline except where indicated[49]
Test ESC (n = 125) CIT (n = 112) PLA (n = 114)
baseline wk10 baseline wk10 baseline wk10
Panic attack frequency per week 5 –1.61* 4.9a –1.43a 5.1 –1.32a
P&A total 25 –8.9**a 24.6a –7.4**a 25 –3.9a
Mean anticipatory anxiety duration (% of time) 45.7 –24.3**a 44.7a –22.1a 42.4 –11.7a
HAM-A score 15.6a –5.9* 15.6a –4.9a 17.6a –4.8
CGI-I score 2.2**b 2.2**a 2.8b
CGI-P score 2.5**b 2.6**a 3.1b
CGI-S score 4.3 –1.6** 4.3a –1.5*a 4.4 –1.2
PGE score 2.3**b 2.2**a 2.8b
a a
QOL score 52.7 5.7** 53.1 5.8* 52.7 2.8a
a Data on file.[51]
b Value at study end.
CGI-I = Clinical Global Impressions Improvement scale; CGI-P = Clinical Global Impressions Phobic Avoidance scale; CGI-S = Clinical
Global Impressions Severity scale; HAM-A = Hamilton Rating Scale for Anxiety; P&A = Panic and Agoraphobia scale; PGE = Patient Global
Evaluation; QOL = quality-of-life questionnaire; * p ≤ 0.05, ** p < 0.01 vs PLA.

headache, influenza-like symptoms, back pain and
upper respiratory tract infections were experienced
by >2% of patients who received escitalopram in the
other trial, although these events were not signifi-
cantly more frequent than in patients who received
placebo.[40] The incidence of nausea in these two
trials decreased after 2 weeks. Most events were
mild[39] or mild to moderate[40] in severity.
The incidence of overall adverse events in these
two trials was similar for escitalopram 10 mg/day
and placebo (79.0%[39] and 58.6%[40] vs 70.5%[39]
and 55.6%[40]) as were the discontinuation rates due
to adverse events (4.2%[39] and 4.7%[40] vs 2.5%[39]
and 1.1%[40]). However, there were significant dif-
ferences in adverse events reported (85.6% vs
70.5%; p < 0.01) and discontinuations (10.4% vs
2.5%; p ≤ 0.05) in patients treated with escitalopram
20 mg/day versus those treated with placebo in one
trial.[39] The incidence of treatment discontinuations
and adverse events were similar in groups receiving
escitalopram 20 mg/day and RS-citalopram 40 mg/
day.[39]
Fewer patients receiving escitalopram 10 or 20
mg/day withdrew because of adverse events than
those receiving venlafaxine XR 75 or 150 mg/day
(8% vs 11%) in an 8-week, double-blind study (sec-
tion 4.1). In addition, the most common treatment-
emergent adverse event, nausea, was significantly (p
< 0.05) more frequent in patients receiving venla-
faxine XR than escitalopram as were increased
sweating and constipation.[45] At the end of the
study, patients underwent a 1-week run-out period
during which those on a high dosage (escitalopram
20 mg/day or venlafaxine XR 150 mg/day) received

Table VI. Cost per success (remission at month 6) for two pharmacoeconomic studies and cost-utility data for one, comparing escitalopram
with RS-citalopram, fluoxetine and venlafaxine as treatment for major depression
Escitalopram RS-citalopram Fluoxetine Venlafaxine
Finnish study (euro; 2000 costs)[52]
Cost-effectivenessa 6516 8555 8542 6984
Cost per QALY 10 148 13 003 12 983 10 825

Swedish study (SEK; date not specified)[53]

Cost-effectivenessa 24 677 32 972 33 421 27 136
a Calculated by dividing cost of treatment by the percentage of remitters at month 6.
QALY = quality-adjusted life-year gained; SEK = Swedish krona.

 Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (5)
Escitalopram: A Review 357

25 PLA
CIT 40 mg/day
Percentage of patients with adverse events

ESC 10 mg/day
20 ESC 20 mg/day

15

10

0
Nausea Diarrhoea Insomnia Dry mouth Ejaculation disorder
(male patients)
Fig. 5. Tolerability of escitalopram (ESC) in major depressive disorder (MDD). Adverse events reported in an 8-week, double-blind trial in
491 patients who fulfilled the DSM-IV criteria for MDD and who were randomised to receive RS-citalopram (CIT) 40 mg/day (n = 125), ESC
10 mg/day (n = 119), ESC 20 mg/day (n = 125) or placebo (PLA) [n = 122].[39]

a low dosage (escitalopram 10 mg/day or venlafax-
ine XR 75 mg/day for 4 days then placebo for 3
days) and those on a low dosage of either drug
received placebo for the whole week. Discontinua-
tion emergent signs and symptoms scores were eval-
uated at this time.[45] Patients who received escitalo-
pram showed fewer discontinuation emergent signs
and symptoms than patients who received venlafax-
ine as measured by a score of ≥4 (p < 0.01).[45]
6.1.2 As Maintenance Therapy
In a 52-week safety extension study in 588 pa-
tients with MDD, almost three-quarters (n = 437)
completed the study.[44] Adverse events were the
main reason for discontinuations (8.8%), with the
majority considered mild to moderate by investiga-
tors. There were no new adverse events in long-term
treatment with escitalopram compared with shorter-
term studies and the adverse event profile was simi-
lar to that observed in the lead-in studies. No clini-
cally significant findings relating to vital signs for
patients switched from RS-citalopram to escitalo-
pram were observed.
6.2 In Anxiety Disorders
The adverse event profile from three trials in
patients with GAD, SAD or panic disorder (section
4.2) receiving escitalopram 10 or 20 mg/day was
similar to that observed in patients with MDD.[47-49]
The withdrawal rate because of adverse events was
low and similar to that of placebo in both trials
reporting this (table VII).[48,49] Nausea was the only
adverse event reported in all three studies.
7. Dosage and Administration
The recommended starting dosage for patients
with MDD is 10 mg/day which, depending on the
individual patient response, may be titrated to a
maximum dosage of 20 mg/day.[20,21] In Europe,
escitalopram is also approved for the treatment of
panic disorder with or without agoraphobia;[21] the
recommended initial dosage is 5 mg/day for 1 week
then titrated to 10 mg/day. The dosage may be
further increased to 20 mg/day, dependent on patient
response to treatment. Administration is once daily
in the morning or evening and escitalopram may be
taken with or without food.[20]
There are reports of serious, sometimes fatal
reactions in patients receiving SSRIs in combination
with monoamine oxidase inhibitors (MAOIs). Simi-
lar reactions have been observed in patients who
have recently discontinued SSRI treatment. Escita-
lopram is, therefore, contraindicated in combination
with MAOIs and a period of at least 2 weeks should
be allowed between discontinuation of escitalopram

 Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (5)
358 Waugh & Goa

Table VII. Treatment-emergent adverse events experienced by patients with generalised anxiety disorder (GAD), panic disorder (PD) or
social anxiety disorder (SAD) receiving escitalopram (ESC) 10 or 20 mg/day or placebo (PLA) for 8–12 weeks in three studies.[47-49] Figures
are percentages
Adverse event GAD[47]a PD[49] SAD[48]
ESC (n = 124) PLA (n = 119) ESC (n = 128) PLA (n = 177) ESC (n = 181)
Nausea 3 13b 13b 12 22
Fatigue 9 13b 9 14
Somnolence 3 6 8b 5 10
Insomnia 3 14 14
Diarrhoea 3 5 9
Increased sweating 2 6
Ejaculation disorder 3 0 6
Decreased libido 1 6
Dry mouth 3 4b 8b
Headache 3 15 16
Withdrawal due to adverse event 8 6 4.5 8.8
a Adverse events in patients with GAD receiving placebo (n = 128) were not reported.
b Data on file.[51]

and commencement of the MAOI or between dis- 8. Place of Escitalopram in the

continuation of the MAOI and commencement of Management of Major Depressive and
escitalopram treatment.[20,21] Anxiety Disorders

Coadministration with St John’s wort (Hyper-

icum perforatum) may result in an increased inci-
dence of adverse reactions. Caution is also advised
in the coadministration of escitalopram and lithium
or drugs metabolised by CYP2D6.[20]
Escitalopram is not indicated for use in paediatric
patients as the safety and efficacy of the drug in this
population has not been examined. Caution is also
advised in pregnant women; escitalopram should
only be used during pregnancy if the potential bene-
fits justifies the potential risk to the fetus, which has
not been established.[20]
In elderly patients or patients with hepatic im-
pairment, the maximum recommended dosage is 10
mg/day.[20,21] In Europe it is recommended that treat-
ment be initiated at 5 mg/day in these patients.[21] No
dosage adjustment is required in patients with mild
to moderate renal impairment; however, escitalo-
pram should be used with caution in patients with
severe renal impairment (creatinine clearance <1.8
L/h; <30 mL/min) [section 3.4].[21]
8.1 In Major Depressive Disorder
Management of depression includes both psy-
chological and pharmacological interventions.[7]
Maintenance therapy significantly reduces relapse
rate and progression to the chronic cycle of remis-
sion and relapse of many patients with depres-
sion.[6,56] Psychological intervention includes cogni-
tive-behaviour therapy, interpersonal psychotherapy
and counselling;[7] however, clinical guidelines for
first-line treatment of initial acute-phase depression
recommend pharmacotherapy.[57,58]
The main classes of antidepressant drugs are
MAOIs, the SSRIs, noradrenergic agents and ser-
otonergic/noradrenergic agents (tricyclic antide-
pressants [TCAs]).[15,59] Most classes of antidepres-
sant drugs have similar efficacy in resolving acute
episodes of depression; however, they differ in their
tolerability profiles.[7] In the past 15 years, SSRIs
have taken over from TCAs as first-line treatment
because of their relatively benign tolerability
profiles.[7,12,15,16] The serious cognitive, cardiac and
other somatic adverse events associated with TCAs
are absent with SSRIs[16] and as a result SSRIs are

 Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (5)
Escitalopram: A Review
prescribed to the majority of patients treated with
antidepressants (60% in the US in 1993/94).[60]
Escitalopram is the pharmacologically active S-
enantiomer of RS-citalopram. It is available for
treatment of MDD in the US[20] and MDD and panic
disorder with or without agoraphobia in Europe.[21]
Escitalopram clearly improves symptoms of depres-
sion, as demonstrated in well designed, 8-week,
placebo-controlled trials using standard assessments
(e.g. MADRS, CGI-I and CGI-S) [section 4.1]. At
least half of treated patients respond to the drug in
dosages of 10 or 20 mg/day (response rate is com-
monly >50%), and efficacy is consistently evident
within 1 or 2 weeks of starting treatment. This may
be an advantage with escitalopram, as a rapid onset
of effect is desirable in patients with depressive
illness.[54]
However, trials comparing this aspect of the pro-
file of escitalopram with that of other SSRIs are few
at present and not all are fully published. Pooled
analysis of three similar 8-week trials[50] comparing
escitalopram with RS-citalopram found a better effi-
cacy and speed of onset of action for escitalopram
and current data suggest that the drug is at least as
effective as venlafaxine XR in short-term (8-week)
trials, although there is some evidence that response
and remission are achieved faster with escitalopram
than with venlafaxine XR (section 4.1.1).[45] In addi-
tion, escitalopram 10 mg/day was more effective
than RS-citalopram 20 mg/day in moderately de-
pressed patients over a 24-week period,[46] sug-
gesting particular efficacy in this subgroup at half
the dosage of the racemic drug.
Effective maintenance therapy is essential to pre-
vent recurrence of depressive symptoms. Escitalo-
pram reduced relapse and increased remission rates
in long-term (36- and 52-week) trials, one of which
was placebo controlled (section 4.1.2).[43,44]
The tolerability profile of escitalopram is predict-
able and similar to that of RS-citalopram. Such
adverse effects as nausea, ejaculatory problems,
headache, diarrhoea and insomnia are expected but,
with the exception of nausea and ejaculatory prob-
lems, were generally no more frequent than with
placebo in fully published clinical trials (section 6).
 Adis Data Information BV 2003. All rights reserved.
359
However, escitalopram may produce less nausea
and caused fewer discontinuations than venlafaxine
XR in one short-term trial.[45] No new adverse ef-
fects have emerged during long-term treatment (up
to 52 weeks) [section 6.1.2].
RS-citalopram is a less potent inhibitor of
CYP2D6 in vitro than other SSRIs and appears to
have relatively low potential for interaction with
other drugs metabolised by this enzyme.[23] Investi-
gations specific to escitalopram are few (section 3.4)
but predict a modest CYP2D6 inhibitory effect and
an increase in the AUC of drugs such as desipra-
mine. Caution is recommended when coadminister-
ing escitalopram with drugs metabolised via the
CYP2D6 pathway.[20] Nonetheless, escitalopram is
expected to lack significant interactions with anti-
psychotic agents as is the case with RS-citalo-
pram,[61] a potentially important benefit when man-
aging patients with depression and comorbidities.
Other factors to consider when selecting an SSRI
for therapy of depression are cost and QOL. The few
data available indicate that escitalopram improves
QOL more than placebo (section 4.1.1). Findings
from two pharmacoeconomic analyses conducted in
Scandinavia found escitalopram to be more cost
effective than RS-citalopram, fluoxetine or venla-
faxine (section 5);[52,53] however, these studies may
have limited use elsewhere because of pricing dif-
ferences. In addition, no trials have specifically in-
vestigated the efficacy of escitalopram in elderly or
adolescent patients, two major subgroups of patients
with MDD.
8.2 In Anxiety Disorders
In addition to being the established treatment for
MDD, SSRIs have well documented efficacy in the
treatment of anxiety disorders.[12] A large number of
patients (up to 67%) with a lifetime diagnosis of
major depression also fulfil the DSM-IV criteria for
anxiety disorder.[12,62-64] Comorbidity of anxiety
with depression is associated with poor outcome and
increased severity of the disorder.[62] It has been
suggested that depression and anxiety disorders may
be separate manifestations of a single underlying
CNS Drugs 2003; 17 (5)
360
cause,[63] which may explain the efficacy of antide-
pressant drugs in the treatment of anxiety disorders.
Treatment for the anxiety disorders has tradition-
ally been with TCAs and benzodiazepines but these
have largely been replaced by SSRIs, which are now
considered first-line treatment and the most appro-
priate treatment for depression and comorbid anxie-
ty disorders.[63] Escitalopram reduces anxiety symp-
toms in patients with GAD,[39,47] SAD[48] and panic
disorder[49] as shown in single studies in each disor-
der; trials were of 8–12 weeks’ duration (section
4.2). The adverse events profiles from these trials
were similar to those observed in trials in patients
with MDD or in patients with anxiety disorders
receiving placebo (section 6.2).[47-49] There are,
however, no long-term data for these indications and
no comparisons with other therapies. In addition,
QOL data, which showed significant improvements
for patients who received escitalopram versus those
who received placebo, are only reported in the panic
disorder trial.
8.3 Conclusion
Escitalopram, the S-enantiomer of RS-citalo-
pram, is a highly selective inhibitor for the serotonin
transporter, ameliorates depressive symptoms in pa-
tients with MDD at half the RS-citalopram dosage,
has a rapid onset of symptom improvement and has
a predictable tolerability profile of generally mild
adverse events. Like RS-citalopram, escitalopram is
expected to have a low propensity for drug interac-
tions, a potential benefit in the management of pa-
tients with comorbidities. In combination, these
properties place escitalopram, like other SSRIs, as
first-line therapy in patients with MDD. Escitalo-
pram is indicated for use in patients with panic
disorder in Europe and, should further evidence
confirm early findings that escitalopram reduces
anxiety, the drug may well find an additional role in
the management of anxiety disorders.
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Correspondence: John Waugh, Adis International Limited,
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Auckland 10, New Zealand.
E-mail: demail@adis.co.nz
CNS Drugs 2003; 17 (5)