Drug Evaluation

Escitalopram
William J Burke
University of Nebraska Department of Psychiatry, 985580 Nebraska Medical Center, Omaha, NE
68198-5580, USA

1. The burden of depression

Escitalopram oxalate (S-citalopram, Lexapro™), a selective serotonin re-uptake
inhibitor antidepressant which is the S-enantiomer of citalopram, is in clinical
2. Introduction to escitalopram/
development worldwide for the treatment of depression and anxiety disor-
chemistry
ders. Preclinical studies demonstrate that the therapeutic activity of citalo-
3. Pharmacology pram resides in the S-isomer and that escitalopram binds with high affinity to
4. Pharmacokinetics and the human serotonin transporter. Conversely, R-citalopram is ∼ 30-fold less
metabolism potent than escitalopram at this transporter. Escitalopram has linear pharma-
5. Clinical efficacy cokinetics, so that plasma levels increase proportionately and predictably with
6. Safety and tolerability increased doses and its half-life of 27 – 32 h is consistent with once-daily dos-
ing. In addition, escitalopram has negligible effects on cytochrome P450 drug-
7. Conclusions
metabolising enzymes in vitro, suggesting a low potential for drug–drug
8. Expert opinion
interactions. The efficacy of escitalopram in patients with major depressive
disorder has been demonstrated in multiple short-term, placebo-controlled
clinical trials, three of which included citalopram as an active control, as well
as in a 36-week study evaluating efficacy in the prevention of depression
relapse. In these studies, escitalopram was shown to have robust efficacy in
the treatment of depression and associated symptoms of anxiety relative to
placebo. Efficacy has also been shown in treating generalised anxiety disorder,
panic disorder and social anxiety disorder. Results also suggest that, at compa-
rable doses, escitalopram demonstrates clinically relevant and statistically sig-
nificant superiority to placebo treatment earlier than citalopram. Analysis of
the safety database shows a low rate of discontinuation due to adverse
events, and there was no statistically significant difference between escitalo-
pram 10 mg/day and placebo in the proportion of patients who discontinued
treatment early because of adverse events. The most common adverse events
associated with escitalopram which occurred at a rate greater than placebo
include nausea, insomnia, ejaculation disorder, diarrhoea, dry mouth and
somnolence. Only nausea occurred in > 10% of escitalopram-treated patients.

Keywords: anxiety, citalopram, depression, escitalopram, S-citalopram

Expert Opin. Investig. Drugs (2002) 11(10):1477-1486

1. The burden of depression

Depression is a common disorder that is associated with considerable morbidity, as

well as social and economic costs. In the US and Europe, the lifetime prevalence of
depression is estimated to be 16 – 17% [1,2] and the years of disability associated
with the disorder exceed those associated with other chronic diseases [3].
Depression is now recognised as a relapsing and recurring disorder for many
patients. While acute antidepressant treatment can effect remission from a depres-
sive episode, current practice guidelines [4] recommend at least 6 months of continu-
ation treatment to consolidate response and prevent relapse. Patients with a history
of depression may require long-term maintenance treatment to prevent recurrence.
The treatment of depressive disorders may be further complicated when patients
Ashley Publications present with multiple symptoms or with comorbid disease. Anxiety symptoms, for
www.ashley-pub.com example, are present in ∼ 70% of patients with a depressive disorder [5]. Depression
has also been reported as a complicating factor in the treatment of some chronic

2002 © Ashley Publications Ltd ISSN 1354-3784 1477

Escitalopram

conditions, including coronary artery disease [6], Parkinson’s The selectivity of escitalopram for SERT was further eluci-
disease [7,8] and AIDS [9,10], necessitating the use of an antide- dated in a comparison of escitalopram with other currently
pressant with minimal risk of drug interactions. available SSRIs for binding affinities at the human 5-HT,
Selective serotonin (5-HT) re-uptake inhibitor (SSRI) antide- noradrenaline (NA) and dopamine transporters, as well as sev-
pressants have had a significant impact on the treatment of eral neurotransmitter receptors [18]. Escitalopram was found
depression, predominantly because of the improved safety and to be not only a potent inhibitor of 5-HT uptake, with ∼ 30-
tolerability profile of the SSRIs relative to tricyclic antidepres- fold more potency than R-citalopram, but also the most
sants [11]. However, SSRIs are heterogeneous, and the notion that SERT-selective compound tested. Furthermore, escitalopram
it may be possible to further improve upon currently available showed little or no affinity for > 150 neurotransmitter recep-
SSRIs as the result of ‘chiral switching’ (i.e., evaluation of a single tors, including the D1 and D2, 5-HT1A and 5-HT 2A, adrener-
isomer of a marketed, racemic product) is now being explored. gic α1, α2 and β, histamine H1 and muscarinic receptors that
contribute to side effects associated with other psychotropic
2. Introduction to escitalopram/chemistry medications. Of interest, the moderate affinity of citalopram
for the histaminergic H1 receptor has now been shown to be
Escitalopram is the S-enantiomer of the SSRI citalopram, a attributable to its R-isomer.
racemic compound that has been used worldwide to treat
∼ 40 million patients, and is known to be a safe, effective and 3.2 Animal models of depression: drug potency
well-tolerated antidepressant [12]. In the resident-intruder model, resident rats behave aggres-
Citalopram is a mixture of R- and S-enantiomers in equal sively when exposed to unfamiliar intruders. Using this
proportions. Hyttel et al. observed [13] that the desired phar- model to test the effect of acute antidepressant treatment to
macological effect of citalopram to inhibit 5-HT re-uptake suppress aggressive behaviour can provide a measure of drug
resides in the S-enantiomer. Escitalopram is more than twice potency. In a study of the effect of escitalopram on rodent
as potent an inhibitor of 5-HT uptake in rat brain synapto- behaviour in this model [19], resident rats were pretreated
somes than citalopram. By comparison, in these experi- with acute, subcutaneous citalopram or escitalopram. Thirty
ments, the R-enantiomer of citalopram was 167 times less minutes later, the animals were confronted with an intruder.
potent than escitalopram. Ethological analysis of the subsequent behaviours indicated
Known chemically as (S)-(+)-1-[(3-dimethyl-amino)pro- that escitalopram reduced aggressive behaviour in rodents in
pyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile oxalate, escita- a dose-dependent manner and increased flight behaviour
lopram was developed jointly by the Danish pharmaceutical without modifying generalised behavioural responses, such
company H. Lundbeck A/S and Forest Laboratories, Inc., (US) as exploration, investigation and sexual behaviour (p < 0.05
for the treatment of depression and other psychiatric disorders. on all dose levels). Citalopram also significantly increased
flight-submit behaviour at all doses examined (p < 0.05),
3. Pharmacology but only reduced aggressive behaviour at a dose of 1 mg/kg,
the highest dose tested (p < 0.05). Results of the study indi-
Development of the single isomer of the SSRI citalopram was cated that escitalopram was at least twice as potent as citalo-
motivated by the finding that the 5-HT re-uptake inhibitory pram in this model.
activity of citalopram resides in its S-enantiomer. In vitro
[13,14] and in vivo [15,16] studies suggest that escitalopram is a 3.3 Animal models of depression: onset of effect
highly selective 5-HT transporter (SERT) inhibitor. Escitalopram (5 and 10 mg/kg s.c.) was also evaluated for its
Microdialysis data have shown that escitalopram, but not ability to reverse anhedonia in the chronic mild stress (CMS)
R-citalopram, increases extracellular 5-HT levels in rat frontal model of depression in rats [20,21], which has been used as a
cortex. Furthermore, R-citalopram has been shown to inhibit measure of onset of antidepressant effect. In this model, pro-
escitalopram-induced increases in extracellular 5-HT levels in longed antidepressant treatment over several weeks is required to
the frontal cortex of freely moving rats [17]. These findings reverse stress-induced behavioural deficits. Treatment with escit-
predict superior clinical efficacy and earlier time to onset for alopram reversed a CMS-induced decrease in sucrose intake to a
escitalopram relative to citalopram. As will be discussed, these similar extent as other antidepressants, yet escitalopram had a
predictions proved to be correct. substantially faster onset of effect. The first significant effects of
both escitalopram doses (p < 0.05) were seen within the first
3.1 Serotonin transporter selectivity week, compared with the 3 – 4 weeks that are typically required
Analysis of the effect of escitalopram and citalopram on neu- before significant effects with antidepressants, such as imi-
ronal activity of 5-HT cells in the rat dorsal raphe nucleus pramine, are noted [22].
(DRN) demonstrates that, while escitalopram and citalopram
dose-dependently decreased the firing activity of 5-HT cells 3.4 Animalmodels of anxiety
in the DRN, escitalopram is twice as potent as citalopram and The anxiolytic potential of escitalopram was assessed in
R-citalopram is inactive in the study model [16]. rodent models of generalised and panic anxiety [23]. Escitalo-

1478 Expert Opin. Investig. Drugs (2002) 11(10)

 Burke

Table 1. Pharmacokinetic parameters and plasma concentration-time profiles for escitalopram in male subjects
(n = 24) administered 40 mg citalopram or 20 mg escitalopram [25].

Treatment

Escitalopram S-DCT
40 mg citalopram 20 mg escitalopram 40 mg citalopram 20 mg escitalopram

Cmax (ng/ml) 21.1 ± 5.5 18.8 ± 4.5 3.5 ± 1.2 3.4 ± 1.0*
Tmax (h) 3.2 ± 2.4 3.0 ± 1.5 14.2 ± 9.7 14.0 ± 11.3*
AUC0-inf (h/ng/ml) 685 ± 376 637 ± 356 349 ± 81* 335 ± 78*
t1/2 plasma (h) 26.3 ± 10.8 26.7 ± 10.9 55.6 ± 13.4* 58.5 ± 14.6*
CL/F (l/h) 36.4 ± 16.0 39.6 ± 18.0 NA NA
Dose in urine (%) 7.9 ± 4.6 8.0 ± 4.8 9.9 ± 2.0 9.6 ± 1.9
*Pharmacokinetic parameters (mean ± SD) were only determined for 23 subjects due to plasma concentrations below the limit of quantification for one subject.
AUC: Area under the curve; CL/F: Apparent oral clearance; C max: Maximum concentration; NA: not applicable: S-DCT: S-demethylcitalopram; t1/2: Half-life;
Tmax: Peak plasma concentration.

pram exhibited a significant anxiolytic-like profile over a Like citalopram, the pharmacokinetics of escitalopram are
broad dose range (0.0001 – 0.1 mg/kg, p < 0.05) in the two- linear and dose-proportional in a dose range of 10 – 30 mg/day.
compartment, black and white box model of generalised In a study involving 29 depressed patients [26], plasma levels of
anxiety. In the footshock-induced ultrasonic vocalisation citalopram and its enantiomers were monitored after the admin-
(USV) model of panic anxiety, escitalopram inhibited USV istration of varying doses of citalopram (20 – 80 mg/day).
potently and completely. Thus, escitalopram exhibits a Plasma levels of escitalopram increased proportionately and pre-
favourable anxiolytic profile in animal models. Conversely, dictably with increased doses.
R-citalopram was inactive or showed only weak activity in
the same models. 4.1 P450 drug metabolising enzyme system
The biotransformation of escitalopram to its metabolites via
4. Pharmacokinetics and metabolism the cytochrome (CYP) P450 drug-metabolising system has
been examined through in vitro analyses of human liver
Escitalopram is rapidly absorbed after oral administration. microsomes. von Moltke et al. [27] reported that escitalopram
Maximal plasma concentrations have been noted approxi- is biotransformed to its principle demethylated metabolite, S-
mately 4 h after dosing [24]. Escitalopram has a plasma elimi- DCT, by three distinct human CYP isoforms in parallel
nation half-life (t1/2) of 27 – 32 h, which is consistent with (CYP3A4, CYP2C19 and CYP2D6). As a consequence, it is
once-daily dosing [24]. unlikely that impaired activity of any one of these isoforms
The pharmacokinetics of escitalopram and its metabolites, due to a drug interactor or because of a genetic ‘poor metabo-
S-demethylcitalopram (S-DCT) and S-didemethylcitalopram lism’ polymorphism would have a large effect on metabolic
(S-DDCT), were compared after single oral doses of clearance. With respect to effects of escitalopram to inhibit
40 mg citalopram and 20 mg escitalopram in a randomised CYP isoenzymes, it has been shown in vitro that escitalopram
crossover trial involving 24 healthy males [25]. Pharmacoki- is a weak or negligible inhibitor of human CYP1A2,
netic parameters (Table 1) for escitalopram and its primary CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, sug-
metabolite were similar regardless of whether escitalopram or gesting that escitalopram has a low likelihood of being
citalopram was administered, indicating that 20 mg escitalo- involved in clinically important pharmacokinetic drug inter-
pram is bioequivalent to 40 mg citalopram with regard to actions in humans [27].
escitalopram plasma concentrations. The minimal potential of escitalopram for involvement in
In the same study, researchers noted no significant differ- clinically important drug interactions was further elaborated
ence in renal clearance, the amount of drug excreted in the in an open-label, three-way, crossover study [28] involving
urine, in dose percentage excreted in urine or urinary t1/2 21 healthy volunteers. The study determined the risk of inter-
for escitalopram or S-DCT following administration of a action between escitalopram and the protease inhibitor riton-
single dose of 40 mg citalopram and 20 mg escitalopram. avir, a potent inhibitor of the CYP3A4 isozyme that may
Moreover, data on plasma and urine concentrations markedly increase serum concentrations of drugs metabolised
revealed no interconversion from the S-enantiomer of cita- by P450 enzymes [29]. Results from plasma and urine analyses
lopram to the R-enantiomer after administration of escita- showed that coadministration of escitalopram had no effect
lopram to humans. on the pharmacokinetics of ritonavir, nor did ritonavir signifi-

Expert Opin. Investig. Drugs (2002) 11(10) 1479

Escitalopram

Treatment week

2 4 6 8
0

Placebo

Escitalopram 10 mg/day

Escitalopram 20 mg/day
Change from baseline

-5
Citalopram 40 mg/day

*
*
-10
*
*

p ≤ 0.05
* ** *

** p < 0.01 ** **

**
-15

Figure 1. Mean change from baseline (LOCF) on the MADRS in depressed patients treated with 10 or 20 mg/day
escitalopram, 40 mg/day citalopram or placebo [31].
LOCF: Last observation carried forward; MADRS: Montgomery Asberg Depression Rating Scale.
cantly affect the pharmacokinetics of escitalopram. The find- A second fixed-dose study of escitalopram in MDD
ings suggest a low potential for interactions between included 491 out-patients experiencing a diagnostic and sta-
escitalopram and agents that inhibit CYP3A4. tistical measurement of mental disorder (DSM)-IV major
depressive episode ≥ 4 weeks duration [31]. Patients, aged 18 –
5. Clinical efficacy 65 years, were treated with 10 or 20 mg/day escitalopram,
40 mg/day citalopram or placebo. At study end point (last
5.1 Depression observation carried forward [LOCF] analysis), both study
The efficacy of a fixed-dose of 10 mg/day of escitalopram doses of escitalopram and 40 mg/day citalopram produced
versus placebo was evaluated in a double-blind, parallel- statistically significant decreases from baseline that were supe-
group study involving 380 patients with major depressive rior to placebo in all measures of depression using the
disorder (MDD) under treatment in primary care centres MADRS, 24-item Hamilton Depression Rating Scale
[30]. During the 8-week treatment period, patients received (HAMD), CGI scales, Hamilton Anxiety scale (HAMA) and
either 10 mg escitalopram or placebo as a single daily dose. patient-rated quality of life scales. Both escitalopram dose
The primary efficacy analysis, the mean change in the Mont- groups achieved significant separation from placebo at early
gomery Asberg Depression Rating Scale (MADRS) total time points on MADRS (Figure 1) and other key variables,
score from baseline, showed a significantly larger effect for and treatment effect was maintained through the study end
escitalopram than for placebo, with a treatment difference of point. Differences between escitalopram and citalopram were
2.7 points (p = 0.002) noted at week 8. Escitalopram was not statistically significant, but escitalopram 10 mg/day was at
statistically superior to placebo from week 2 onwards. In least as effective as 40 mg/day citalopram, and trends towards
additional by-week analyses, escitalopram was associated greater superiority of 20 mg/day escitalopram over 40 mg/day
with a consistently statistically significantly superior effect citalopram were present [31].
than placebo beginning at week 1 in the Clinical Global Although fixed dose trials are useful for determining the min-
Impression Improvement (CGI-I) score, week 2 in the imal effective dose of a drug and elucidating its dose-response
MADRS score and week 3 in the Clinical Global Impression properties, such dosing regimens are not representative of a
Severity (CGI-S) score. drug’s pattern of use in normal clinical practice. Experience with

1480 Expert Opin. Investig. Drugs (2002) 11(10)

 Burke

flexibly-dosed escitalopram is available from two similarly were considered to have responded to treatment based on a
designed, randomised, double-blind, placebo-controlled trials 50% or greater change in MADRS score from baseline. The
in which escitalopram and citalopram were compared with pla- difference between both the escitalopram and citalopram arms
cebo treatment in out-patients with major depressive disorder and placebo was statistically significant (p < 0.001). Escitalo-
[32]. A total of 844 patients were randomised to double-blind pram treatment also significantly improved CGI-I scores within
treatment with placebo (n = 281), escitalopram 10 – 20 mg/day 1 week (p < 0.001, compared with placebo), whereas citalo-
(n = 280) or citalopram 20 – 40 mg/day (n = 283). At end pram treatment showed significant improvement in CGI-I
point, both escitalopram and citalopram produced significant scores at week 4 (p < 0.05, compared with placebo).
improvement relative to placebo in MADRS, CGI-I and CGI-S When the subset of patients in the pooled population who
scores. Consistent with findings from the fixed dose study [31], were severely depressed upon entering the trials (baseline
the escitalopram treatment group showed statistical superiority MADRS ≥ 30) were considered, escitalopram treatment was
to placebo at an earlier timepoint than the citalopram group, statistically significantly superior to citalopram treatment at
separating from placebo on all efficacy measures after week 1. weeks 1, 6 and 8.
The proportion of patients who met criteria for response
(≥ 50% reduction in MADRS score relative to baseline) was sig- 5.3 Depression relapse
nificantly higher in both active treatment groups relative to pla- The efficacy of escitalopram in preventing relapse of depressive
cebo (p < 0.05). The mean daily dose of study medication was symptoms after a depressive episode has resolved was examined
12.6 mg/day for escitalopram and 25.5 mg/day for citalopram. in a 36-week extension study [36] involving 274 depressed out-
patients (male or female, 18 – 81 years) who previously had
5.2 Pooled analysis of escitalopram/citalopram data completed 8 weeks of randomised, double-blind treatment
As described, three double-blind, placebo-controlled trials of with escitalopram, citalopram or placebo. The extension study
escitalopram in MDD included citalopram as an active con- initially consisted of an 8-week, flexible dose, open-label phase,
trol [31,32]. While none of the three studies was sufficiently in which all patients received 10 – 20 mg/day escitalopram.
powered to detect differences between active treatment During the subsequent randomised, double-blind, placebo-
groups, the observation in all studies of numerically superior controlled, parallel-group phase, patients considered to be
performance of escitalopram compared with citalopram mer- responders (MADRS ≤ 12) were randomly assigned in a
ited further examination. 2:1 ratio to 36 weeks of double-blind treatment with either
The similar design of the three trials allowed for pooling of escitalopram (continued at the same dose) or placebo. At the
the data [33] to evaluate the comparative efficacy of escitalo- time of randomisation, patients had low levels of residual
pram with citalopram, an SSRI that has proven efficacy in depressive symptoms (MADRS scores ∼ 6 – 7). Over the
major depression [34,35]. All of the studies were randomised, course of maintenance treatment, the time to relapse of depres-
double-blind, placebo-controlled evaluations of escitalopram sion (MADRS ≥ 22) was significantly longer and the cumula-
(10 – 20 mg/day) and citalopram (20 – 40 mg/day) in male tive rate of relapse was significantly lower in patients who
or female out-patients ≥ 18 years, who met criteria for MDD received continuation treatment with escitalopram (26% escit-
with a MADRS score of ≥ 22 at baseline. Efficacy analyses alopram versus 40% placebo, hazard ratio = 0.56, p = 0.013).
were based on the pooled intent-to-treat population, which The time to relapse was not correlated with age, sex, race or
included 1321 patients who had received ≥ 1 dose of double- depression history. Continuing treatment with escitalopram
blind study medication and had ≥ 1 postbaseline MADRS resulted in further reduction in mean MADRS total score and
assessment. Analyses were performed on changes from base- significantly decreased the percentage of patients meeting
line in MADRS, MADRS inner tension item (which meas- DSM-IV defined criteria for a major depressive episode, as
ures improvements in associated symptoms of anxiety) and compared with placebo (23% escitalopram versus 35% pla-
CGI-I scores. cebo; p = 0.03, Mantel-Haenszel Chi-Square Test).
In the pooled analysis [33], improvements in depression and
anxiety symptoms on MADRS and CGI-I scores were noted 5.4 Anxiety symptoms in depression
within 1 – 2 weeks of treatment for those patients receiving The three clinical trials that evaluated escitalopram, citalo-
escitalopram compared with placebo. The onset of measurable pram and placebo in the treatment of major depressive dis-
improvement in MADRS and CGI-I scores for citalopram was order [31-33] used the MADRS scale as the primary efficacy
typical of that seen with other antidepressants, with statistically end point. Included in the MADRS total score is the
significant differences between citalopram and placebo begin- MADRS inner tension item, which can provide information
ning at week 4. Over the 8-week treatment period (Figure 2), on the effect of antidepressant treatment on associated
escitalopram treatment produced greater mean changes on symptoms of anxiety.
MADRS than citalopram at all study visits, and was statistically Data pooled from the three studies indicate that treatment
superior to citalopram at several timepoints. Among the active with 10 – 20 mg/day escitalopram and 20 – 40 mg/day cita-
treatment and placebo arms, 59.3, 53.4 and 41.2% of escitalo- lopram was associated with significant improvements in
pram-, citalopram- and placebo-treated patients, respectively, symptoms of anxiety as measured by change from baseline to

Expert Opin. Investig. Drugs (2002) 11(10) 1481

Escitalopram

Treatment week

2 4 6 8 LOCF

Placebo

-4 Citalopram
Change from baseline

Escitalopram
* †

-8
*

-12
**
**
*
**
p < 0.05 versus placebo
*
**
**p < 0.001 versus placebo **
† p < 0.05 versus citalopram
-16 ** †

Figure 2. Mean change from baseline by visit and at end point (LOCF) on the MADRS in depressed patients treated with
escitalopram, citalopram or placebo [33].
LOCF: Last observation carried forward; MADRS: Montgomery Asberg Depression Rating Scale.

end point in the MADRS inner tension item (Figure 3). observed in escitalopram-treated patients as early as week 4
Among escitalopram-treated patients, statistically significant (when the dose was still held at 10 mg/day) and, at end point,
improvements in MADRS inner tension scores were escitalopram treatment was statistically superior to placebo treat-
observed as early as 1 week following initiation of treatment ment on all efficacy measures.
(p < 0.05, compared with placebo), while improvements Similarly, results from a 10-week, randomised, double-
among citalopram-treated patients reached statistical signifi- blind, placebo-controlled, multi-centre trial of escitalopram in
cance at week 4 (p < 0.001, compared with placebo), sug- 237 patients aged 18 – 80 with panic disorder (with or with-
gesting that escitalopram may alleviate anxiety symptoms out agoraphobia) demonstrated that, compared with placebo,
more quickly than citalopram. escitalopram (10 – 20 mg/day) significantly reduced panic
attack frequency and severity, anticipatory anxiety and phobic
5.5 Anxiety disorders avoidance, and significantly improved overall clinical status
Clinical development programs are also underway to evalu- and quality of life [38].
ate the safety and effectiveness of escitalopram for the treat- In a study that compared the efficacy and safety of escita-
ment of other psychiatric disorders, including panic, social lopram (n = 181) to placebo (n = 177) in out-patients aged
anxiety and generalised anxiety (GAD) disorder. Results 18 – 65 years with a primary diagnosis of social anxiety dis-
from initial studies in these patient populations are begin- order, 12 weeks of double-blind treatment with escitalopram
ning to be available. produced statistically greater improvement on the Liebowitz
In an 8-week, double-blind, placebo-controlled trial of escita- Social Anxiety Scale (LSAS) compared with placebo. Sec-
lopram for the treatment of GAD, male or female out-patients ondary efficacy analyses, including the CGI-S, CGI-I, LSAS
aged 18 – 80 years were randomly assigned to receive flexible avoidance and fear/anxiety components and 2/3 items on
doses of escitalopram (10 – 20 mg/day) or placebo [37]. The the Sheehan Disability Scale also showed a significantly bet-
change from baseline in the HAMA was the primary efficacy ter therapeutic effect at end point for escitalopram relative
variable; secondary variables included the CGI, Hospital Anxi- to placebo [39].
ety and Depression Scale (HAD) and Quality of Life Question- These results suggest that escitalopram may possess a broad
naire. Significant improvement compared with placebo was spectrum of efficacy beyond major depression.

1482 Expert Opin. Investig. Drugs (2002) 11(10)

 Burke

Treatment week

2 4 6 8 LOCF

-0.1

-0.3 Placebo
Change from baseline

Citalopram
-0.5
*† Escitalopram
-0.7

-0.9 **

**

-1.1

**
** **
-1.3
* p < 0.05 versus placebo **
** p < 0.001 versus placebo **
**
† p < 0.05 versus citalopram
-1.5 **

Figure 3. Mean change from baseline by visit and at end point (LOCF) on the MADRS inner tension item in depressed
patients treated with escitalopram, citalopram or placebo [33].
LOCF: Last observation carried forward; MADRS: Montgomery Asberg Depression Rating Scale.

6. Safety and tolerability ency of common adverse events among patients who
received fixed doses of 10 and 20 mg/day escitalopram.
In placebo-controlled trials in patients with MDD, escitalo-
pram was very well-tolerated, as measured by the rate of study 7. Conclusions
discontinuation as the result of adverse events [40]. Among
patients treated with escitalopram 10 mg/day, there was no Preclinical studies of escitalopram suggest that the S-enanti-
statistically significant difference between escitalopram and omer of citalopram is the most selective inhibitor of 5-HT
placebo in the proportion of patients who discontinued treat- re-uptake that has been studied to date, and exhibits more
ment prematurely because of adverse events. Overall, < 6% of than twice the potency of the parent compound, citalo-
escitalopram-treated patients (10 – 20 mg/day) compared pram. Escitalopram has also been shown to lack affinity for
with 2.2% of placebo-treated patients discontinued treatment postsynaptic receptors that contribute to side effects associ-
because of adverse events. ated with many other psychotropic drugs. In animal models
Analysis of safety data from four placebo-controlled trials of depression and anxiety, escitalopram demonstrated a
of escitalopram in the short-term treatment of depression consistent and robust effect and it was observed to have a
showed that escitalopram is associated with low crude faster onset of effect than citalopram. Not only does the
adverse events rates overall [40-41]. Table 2 lists the most com- therapeutically relevant activity of citalopram reside in esci-
mon adverse events (occurring in ≥ 5% of escitalopram- talopram, but microdialysis data indicate that R-citalopram
treated patients and at a rate greater than placebo) among inhibits this activity of escitalopram, leading to the predic-
715 patients who received 10 – 20 mg/day of escitalopram tion that escitalopram should be more potent clinically
in placebo-controlled studies of 8 weeks duration. Only than citalopram.
nausea occurred in > 10% of escitalopram-treated patients In pharmacokinetic studies, plasma levels of escitalopram
and just four adverse events (nausea, insomnia, ejaculation increased proportionately and predictably with increased
disorder and somnolence) occurred at a rate ≥ 5% and at doses. Escitalopram has a t1/2 of 27 – 32 h, which is consistent
least twice that of placebo. Table 3 shows the dose-depend- with once-daily dosing, and has shown no or very minimal

Expert Opin. Investig. Drugs (2002) 11(10) 1483

Escitalopram

Table 2. Most common adverse events associated with Table 3. Dose-dependency of common adverse events* in
escitalopram (occurring in ≥ 5% of treated patients and patients receiving placebo or fixed doses of 10 mg/day
at a rate greater than placebo) in placebo-controlled escitalopram or 20 mg/day escitalopram.
trials in major depression.
Adverse Placebo % Escitalopram % Escitalopram %
Adverse event Placebo % Escitalopram % event (n = 311) 10 mg/day 20 mg/day
(n = 592) 10 – 20 mg/day (n = 310) (n = 125)
(n = 715) Insomnia 4 7 14
Nausea 7 15 Diarrhoea 5 6 14
Insomnia 4 9 Dry mouth 3 4 9
Ejaculation disorder* 0 9 Somnolence 1 4 9
Diarrhoea 5 8 Dizziness 2 4 7
Somnolence 2 7 Increased <1 3 8
Dry mouth 5 6 sweating
Dizziness 4 6 Constipation 1 3 6
Influenza-like symptoms 4 5 Fatigue 2 2 6
* Percentages are relative to the number of male patients (placebo n = 188, Indigestion 1 2 6
escitalopram n = 225). Adapted from Gergel et al., APA 2002 [40]. * Adverse events with an incidence rate of ≥ 5% in either escitalopram dose
group and with an incidence rate in the 20 mg/day escitalopram group that was
≥ twice that of the 10 mg/day escitalopram group or the placebo group.
effects on cytochrome P450 enzymes in vitro, indicating a low Reprinted with permission from Gergel et al., APA 2002 [40].
potential for causing drug–drug interactions.
The clinical benefits of escitalopram have been noted in
double-blind, placebo-controlled clinical trials involving SSRIs are seen as efficacious, easy to use and generally well-tol-
patients with major depressive disorder, with and without erated agents (indeed, more easily tolerated than predecessor
attendant symptoms of anxiety. Escitalopram consistently compounds), helping to increase patient compliance with what
demonstrated efficacy over placebo, with partial resolution often is a long-term therapeutic regimen. Despite a common
of symptoms beginning as early as 1 – 2 weeks after initia- mechanism of action, SSRIs are heterogeneous compounds and
tion of therapy and a safety profile generally comparable to differences among SSRIs have been recognised [42,43]. Addition-
placebo. Results from placebo-controlled trials, in which cit- ally, a number of studies have found that patients who are non-
alopram was administered as an active control, suggest that responsive or intolerant to one SSRI may respond well to
at comparable doses, escitalopram may be more effective another [44,45].
than the parent compound, with a more rapid onset of Development of a new antidepressant that is a single iso-
measurable effect and favourable tolerability. Moreover, use mer of an existing agent is a particularly intriguing avenue of
of escitalopram over long-term treatment (36 weeks) signifi- research because it offers the potential to improve upon the
cantly reduced the risk of depression relapse and provided therapeutic index of a well-regarded compound (in this case,
further resolution of depression symptoms. citalopram), by eliminating any detrimental pharmacologi-
Results from initial placebo-controlled studies of escitalo- cal activity associated with the isomer that makes little or no
pram in GAD, panic disorder and social anxiety disorder sug- contribution to the racemate’s therapeutic effects. Escitalo-
gest that escitalopram possesses potent anxiolytic activity in pram, the enantiomer of citalopram, has demonstrated a
addition to its antidepressant effects. robust and consistent effect on symptoms of depression and
anxiety, early onset of measurable effect and a good safety
8. Expert opinion and tolerability profile in clinical trials for major depression
and several anxiety disorders. Based on these data, it appears
The commercial availability of SSRIs has had a significant that escitalopram will be an important addition to the arma-
impact on the management of depressive disorders. As a class, mentarium of drugs for depressive disorders.

1484 Expert Opin. Investig. Drugs (2002) 11(10)

 Burke

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Affiliation
34. FEIGHNER JP, OVERØ K: Multicenter, disorder. 155th Annual Meeting of the William J Burke, MD
placebo-controlled, fixed-dose study of American Psychiatric Association. University of Nebraska Department of Psychiatry,
citalopram in moderate-to-severe Philadelphia, PA, USA (18-23 May 2002). 985580 Nebraska Medical Center, Omaha,
depression. J. Clin. Psychiatry (1999) • Suggests escitalopram is safe, effective, and NE 68198-5580, USA
60:824-830. well-tolerated in the treatment of social Tel: +1 402 354 6591;
anxiety disorder. Fax: +1 402 354 6896;
35. MENDELS J, KIEV A, FABRE LF:
Double-blind comparison of citalopram 40. GERGEL I, HAKKARAINEN H, E-mail: wjburke@unmc.edu

1486 Expert Opin. Investig. Drugs (2002) 11(10)