Therapeutic Advantages of Escitalopram in Depression and Anxiety Disorders
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Abstract
What are the therapeutic advantages
of escitalopram, the purified S-enantio-
mer of the racemate citalopram? The
Clinical Focus biological activity and therapeutic effects
Primary Psychiatry. 2002;9(12):30-35 of citalopram, which has been used for
over a decade to effectively treat depres-
Therapeutic
sion and other psychiatric disorders, have
been shown to reside exclusively in esci-
talopram. Escitalopram has been shown
in vitro to be more than twice as potent as
citalopram in the inhibition of serotonin
Advantages of
uptake. It is the most selective agent in
its class, with virtually no affinity for
other neurotransmitters. The efficacy of
escitalopram in the treatment of depres-
sion has been demonstrated in several
Escitalopram
clinical trials. Sustained improvement in
symptoms of depression was first seen at
1–2 weeks, and continuing improvement
and effective prevention of depressive
relapse were observed during long-term
in Depression
studies. Further, escitalopram has also
been shown to be an effective treatment
for anxiety disorders such as panic dis-
order, generalized anxiety disorder, and
social anxiety disorder. Escitalopram was
and Anxiety
safe and well-tolerated in these studies,
with a low rate of discontinuation due to
adverse events. Finally, escitalopram has
the lowest propensity of all the selective
serotonin reuptake inhibitors, including
Disorders
citalopram, for drug-drug interactions
mediated by cytochrome P450. Together,
these properties make escitalopram an
ideal choice for the treatment of depres-
sion and other psychiatric disorders in
primary care patients, in the elderly, and
in patients with comorbid illness.
Andrew Farah, MD
Introduction
The selective serotonin reuptake
inhibitors (SSRIs) are widely accepted
as first-line therapy for depression, as
well as for anxiety disorders such as
panic disorder (PD), generalized anxi-
ety disorder (GAD), and social anxiety
disorder (SAD). In addition, they have
demonstrated utility in a variety of other
conditions such as premenstrual dys-
phoric disorder, and some chronic pain
syndromes and impulse control disor-
ders. Thus, SSRIs are among the most
prescribed pharmaceutical agents.1
Despite the great utility of the
available SSRIs, research to develop
improved antidepressants continues.
Reported response rates in clinical trials
with the older SSRIs have ranged from
Dr. Farah is medical director of behavioral services at High Point Regional Health System in High Point,
North Carolina. 50% to 60%, meaning that a proportion
Disclosure: The author has received grants and/or consultant fees from Forest Laboratories. of patients may not adequately respond
30 Primary Psychiatry, December 2002Clinical Focus
to the first drug they try.2-4 Additional Pharmacology anxiolytic-like effects in all three mod-
areas of unmet clinical need include Escitalopram is more than twice as els, while R-citalopram was either inac-
better tolerability and long-term effi- potent as citalopram in the inhibition tive or showed weak activity.
cacy, faster onset of action, and better of serotonin uptake in in vitro binding
efficacy for difficult-to-treat conditions studies10 and is the most selective agent Pharmacokinetics
such as severe depression.5 of its class.9-11,13,14 Escitalopram Metabolism of escitalopram to S-
One current area of research shows virtually no affinity for serotonin, demethylcitalopram is meditated by
focuses on developing single-isomer norepinephrine, muscarinic, histamin- three CYP isoforms in parallel (3A4,
products from racemic compounds. ic, and dopamine receptors (Table 1). 2D6, and 2C19), with 3A4 becom-
Approximately 80% of available medi- Escitalopram has been shown to ing more dominant as escitalopram
cations are racemic compounds—mix- be active in several animal models of doses increase.12 Biotransformation of
tures of enantiomers, or stereoisomers depression. For example, chronic mild demethylcitalopram to didemethylci-
that are nonsuperimposable images of stress induces anhedonia in rats, as talopram is mediated by CYP 2D6 and
one another. As one might expect, the measured by a significant decrease an unknown non-CYP-mediated reac-
biological activity of a compound is in sucrose intake. Both escitalopram tion.12 The metabolites of escitalopram
influenced by its stereochemical prop- and citalopram reversed the effects of do not contribute to the clinical effects
erties. For example, since many drugs chronic mild stress, and the onset of of the SSRI as they are present at much
act by adhering to specific receptors, effect in the escitalopram group was lower concentrations and are much
it is no surprise a left-oriented isomer faster than in the citalopram group.15 weaker inhibitors of serotonin reuptake
(“S”) may be a better fit in a particular Further, escitalopram and citalopram in vitro.12 Escitalopram is absorbed
receptor than a right-oriented isomer produced dose-dependant effects, while rapidly, with an average time to peak
(“R”), or vice versa. Thus, single-iso- R-citalopram was inactive, as seen in plasma concentration or serum concen-
mer agents have the potential for an Porsolt’s forced swim test in mice.9 trations of 4 hours. Food does not affect
improved therapeutic index result- Finally, escitalopram was at least twice escitalopram absorption. Escitalopram
ing from higher potency and selectiv- as potent as citalopram in reducing does not bind strongly to plasma pro-
ity, while removing any undesirable aggressive behavior in an antagonistic teins, with approximately 56% of the
effects attributable to the less active behavior model in the rat.16 compound being protein bound.19
enantiomer. This can result in a faster The anxiolytic activity of escitalo- Escitalopram exhibits linear kinetics
onset of action, improved duration pram has also been demonstrated using that are dose-proportional across the
of action, and decreased potential for animal models.16-18 In the first model, therapeutic range. Terminal half-life
drug-drug interactions. Other benefits stimulation of the dorsal periaqueductal in young healthy subjects is about
could include a less complicated phar- grey matter in the rat leads to a panic- 27–32 hours, consistent with once-
macokinetic profile and a simplified like aversive reaction that is considered a-day dosing.19 The metabolites of
relationship between plasma concen- one the most reliable models of panic escitalopram do not have extended
tration and clinical effect. anxiety.18 In the second, foot shock half-lives, so increased accumulation
Escitalopram oxalate is the S-enan- induced ultrasonic vocalization in adult of drug is not observed. Steady state
tiomer of the racemic SSRI antide- rats reflects aspects of panic disorder.17 levels of escitalopram are achieved
pressant, citalopram hydrobromide. Finally, the two-compartment black and within 10 days. In a cross-over study
Citalopram has been demonstrated to white box test in mice and rats repre- comparing the single-dose pharmaco-
effectively treat depression, PD, pre- sents aspects of GAD.17 Escitalopram kinetics of escitalopram 20 mg to those
menstrual dysphoric disorder, and produced potent, dose-dependent of citalopram 40 mg, the two SSRIs
obsessive-compulsive disorder.6-8 The
biological activity and therapeutic Table 1
effects of citalopram have been shown
Receptor-Binding Affinities of SSRIs In Vitro
to reside exclusively in escitalopram.
At physiologic concentrations, the Ki (nM)
5-HT2C α1 Muscarine Histamine H1
R-enantiomer of citalopram has no 3H-Mesulergine 3H-Prazosin 3H-NMS 3H-Pyrilam
activity to inhibit serotonin reuptake—
Porcine Human Human Guinea Pig
the presumed mechanism underlying Escitalopram 2,500 3,900 1,200 2,000
the antidepressant effect of citalopram. Citalopram 2,100 1,200 1,400 280
However, the R-isomer has been shown R-citalopram 1,800 560 2,400 180
to have a weak affinity for histamine H1 Fluoxetine 72 3,200 700 1,500
receptors, and the demethyl metabolite Fluvoxamine 5,800 1,300 31,000 29,000
of R-citalopram weakly inhibits cyto- Paroxetine 9,000 2,700 72 24,000
chrome P450 (CYP) 2D6.9-12 Sertraline 2,300 190 430 6,600
This review summarizes published SSRIs=selective serotonin reuptake inhibitors; Ki (nM)=dissociation constant; 3H=tritiated hydrogen;
escitalopram data demonstrating the NMS=N-methylscopolamine.
drug’s safety and efficacy in the treat-
Adapted from: Owens M, Knight D, Nemeroff C. Second-generation SSRIs: human monoamine
ment of depression and anxiety disor- transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry. 2001;50:345-350.
ders, as well as its potential advantages Farah A. Primary Psychiatry. Vol 9, No 12. 2002.
over older SSRIs.
Primary Psychiatry, December 2002 31Clinical Focus
and their primary metabolites were primary care setting.23 Escitalopram- Flexible Dose
found to be bioequivalent.20 treated patients experienced significant Trivedi and Lepola24 reported the
The pharmacokinetics of escitalo- improvement by study endpoint relative combined results of two 8-week, dou-
pram in elderly subjects (≥65 years) are to placebo on the MADRS total score ble-blind, placebo-controlled studies
similar to those observed in younger (P=.002). Further, escitalopram showed (including 8-week results from the
subjects, although the area under the onset of action that was statistically European study described above15 and
curve (AUC) and half-life were increased superior to placebo from week 1 onward a study in the US of almost identical
by about 50%. Thus, 10 mg/day is the as measured by the CGI-Improvement design) conducted by both special-
recommended dose for elderly patients. scale, at week 2 as measured by MADRS ists and primary care physicians.24
Escitalopram has not been evaluated total score, and from week 3 onward as In these studies, 844 depressed out-
in pediatric patients. No dosage adjust- measured by CGI-Severity (CGI-S) scale. patients were randomized to receive
ment is recommended for patients with Response rates (defined as at least a 50% placebo, escitalopram 10–20 mg/day, or
reduced hepatic function, moderate reduction in MADRS total score) were citalopram 20–40 mg/day. Both active
renal function impairment, or on the 55% for the escitalopram group versus treatment groups experienced signifi-
basis of gender.21 42% for placebo. cant changes from baseline in MADRS
Montgomery and colleagues15 pub- total score. Similar to the fixed-dose
Efficacy in Depression lished results from the first 4 weeks studies, the onset of action in the
Data from several large, randomized, of a European 8-week flexible-dose escitalopram group (1 week) was sig-
placebo-controlled clinical trials indi- study conducted in primary care cen- nificantly faster than the citalopram
cate that escitalopram is effective in the ters, during which the escitalopram group, and changes in mean MADRS
treatment of depression. These studies and citalopram doses were fixed at scores were larger for escitalopram
also indicate that the starting dose of 10 mg/day and 20 mg/day, respectively. than citalopram throughout the study.
10 mg/day is an effective dose to which At week 4, mean change in MADRS The mean change from baseline in
most patients respond, and that escitalo- total score for escitalopram patients CGI-S was significant for escitalopram
pram treatment was significantly supe- was significantly decreased versus pla- at week 1 (PClinical Focus
treats depression. However, none of the n=181) or placebo (n=93) for 36 weeks the Hamilton Rating Scale for Anxiety
three studies employing both placebo- (placebo-controlled withdrawal phase (HAM-A) and the HAM-A psychic anxi-
and citalopram-comparator arms22,24 of the study). In the escitalopram group, ety subscale, the Hospital Anxiety and
was of sufficient sample size to detect time to relapse (defined as a MADRS Depression (HAD) subscale, and the
a difference between active treatments. total score ≥22, or discontinuation due CGI-Severity scale. Further, QOL mea-
Therefore, Gorman25 examined pooled to an insufficient therapeutic response) sures improved, with statistically sig-
data from the three trials that included was significantly longer, and cumulative nificant improvement observed in both
a citalopram arm in order to determine relapse rate was significantly lower than the total scale and in individual items
whether escitalopram represents an with placebo. In addition, continuing assessing overall life satisfaction and
improved treatment for depression rela- treatment with escitalopram produced contentment, ability to function in daily
tive to citalopram. The similar design further improvement in depression life, and mood and overall sense of well
features (eg, patient characteristics, scores versus placebo. being.
symptom measurement scales) of the Escitalopram treatment (10–20 mg/day)
three studies allowed for the pooling of Efficacy in Anxiety Disorders significantly improved QOL and PD
data to provide a sample size adequate Several animal models indicate that symptoms in a 10-week, randomized,
for statistical comparisons between the escitalopram has anxiolytic properties. placebo-controlled, double-blind trial
two active treatment groups. Further, in clinical trials comparing the (N=247).29 Several validated panic and
At study endpoint, both the escitalo- efficacy of escitalopram and citalopram anxiety assessment tools, as well as
pram 10–20 mg/day group (n=520) and in relieving anxiety symptoms associ- the CGI and two patient-rated QOL
the citalopram 20–40 mg/day group ated with depression, escitalopram also scales, indicated that escitalopram
(n=403) experienced significantly had a rapid onset of action,27 which is significantly improved PD symptoms
improved depressive symptoms versus consistent with the other efficacy find- compared to placebo. At weeks 8 and
placebo (P≤.001). Escitalopram treat- ings determined for escitalopram in the 10, significantly more escitalopram-
ment significantly improved MADRS treatment of depression. Results demon- treated patients achieved full remis-
(Figure 2) and CGI scores within strating the efficacy of escitalopram in sion (defined as no panic attacks in
1 week. At week 1 and week 8, esci- the treatment of GAD, PD, and SAD are the previous week and a CGI-I score
talopram treatment led to statistically discussed in the following section. of 1; Figure 3). In addition, significant
significantly greater improvement on Escitalopram 10–20 mg/day signifi- improvement was observed in QOL
the MADRS than citalopram treat- cantly improved symptoms of GAD in scores for escitalopram patients com-
ment (Figure 2). Approximately 60% an 8-week, randomized, double-blind, pared to placebo patients, as well as in
of patients treated with escitalopram placebo-controlled trial (N=252).28 individual items, including overall life
were responders (defined as at least a The escitalopram-treated group expe- satisfaction, social and family relation-
50% reduction in MADRS total score), rienced significant improvement over ships, ability to function in daily life,
while the response rates for citalopram placebo on efficacy measures including and overall sense of well being.
and placebo were 53% and 41%, respec-
tively. Figure 2
Mean Change From Baseline in MADRS Scores in Depressed Patients Treated
Relapse Prevention With Escitalopram, Citalopram, or Placebo
Continuation treatment with esci-
talopram in a long-term, double-blind,
placebo-controlled study effectively
prevented relapse and provided fur-
ther improvement in depressive symp-
toms.26 Two hundred seventy-four
patients who had completed 8 weeks
of double-blind treatment with esci-
talopram, citalopram, or placebo were
enrolled in this long-term extension
study. The first phase of the continu-
ation treatment was an 8-week, flex-
ible-dose, open-label period in which
all patients received escitalopram 10–20
mg/day (patients who had received esci-
talopram in the double-blind lead-in
trials actually received a total of 16
weeks of escitalopram treatment prior
MADRS=Montgomery-Asberg Depression Rating Scale; LOCF=last observation carried forward;
to entering the placebo-controlled with- vs=versus.
drawal phase). Responders during this
Reprinted with permission from: Gorman JM, Korotzer A, Guojin S. Efficacy comparison of escitalo-
8-week treatment period were random- pram and citalopram in the treatment of major depressive disorders: pooled analysis of placebo-
ized in a 2:1 ratio to double-blind treat- controlled trials. CNS Spectrums 2002:7(suppl 1):40-45.
ment with either escitalopram (at the Farah A. Primary Psychiatry. Vol 9, No 12. 2002.
same dose to which they had responded,
Primary Psychiatry, December 2002 33Clinical Focus
Escitalopram 10–20 mg/day was cardiogram, or vital signs. Escitalopram the Swedish Birth Registry of women
effective in the treatment of SAD in a treatment had no effect on body weight, reporting the use of antidepressants
12-week, placebo-controlled, double- unlike other SSRIs. (including citalopram, n=375) in early
blind, multicenter, study (N=358).30 Patients can be reassured that, in pregnancy were not significantly differ-
Escitalopram was significantly supe- cases where escitalopram data are lim- ent from the rest of the registry, with
rior to placebo (P10% of
patients treated with escitalopram and * Full remission is indicated by zero panic attacks in the previous week and a score of 1 on the
more frequently than with placebo. Clinical Global Impressions-Improvement scale.
Point of prevalence estimates of nausea Adapted from: Stahl S, Gergel I, Dayong L. Escitalopram in the treatment of panic disorder.
per day show the difference between Presented at: the National Conference of the Anxiety Disorders Association of America; March
2002; Austin, Tex.
escitalopram and placebo leveling off
Farah A. Primary Psychiatry. Vol 9, No 12. 2002.
after 3–4 weeks of double-blind treat-
ment.23 Escitalopram was not asso-
ciated with central nervous system Table 2
stimulant effects, as the only activation Adverse Events Associated With Escitalopram Treatment
adverse event to occur at a rate greater
than placebo was insomnia (9% versus
Placebo Escitalopram
4%). Incidence of ejaculation disorder
Adverse Event* N=592 N=715
for male patients in the safety database
Nausea 7.4% 14.7%
is approximately 9% for escitalopram, Ejaculation disorder† 0% 9.3%
and is similar to that reported for citalo- Insomnia 3.9% 9.1%
pram.31 Other sexual adverse events, Diarrhea 5.2% 8.1%
such as decreased libido, impotence, Dry mouth 4.6% 6.2%
and anorgasmia, were reported at 4%, Somnolence 1.9% 6.0%
3%, and 2%, respectively.21 Dizziness 2.7% 5.2%
In all the studies reviewed, no clini- * Incidence >5% and >placebo.
† Incidence based on male patients only.
cally significant changes were noted for
clinical laboratory parameters, electro- Farah A. Primary Psychiatry. Vol 9, No 12. 2002.
34 Primary Psychiatry, December 2002Clinical Focus
interactions. According to in vitro and 14 days of discontinuing an MAOI. regular basis, as well as for those with
in vivo data, escitalopram has little or chronic medical illnesses, which often
no effect on the CYP pathways 1A2, Dosage and Administration require extensive polypharmacy. In con-
2C9, 2C19, 2D6, 3A4, and, 2E1 (Table Escitalopram should be adminis- clusion, the data presented here support
3).12 The weak inhibitory activity of tered once daily in the morning or the use of escitalopram as a first-line
citalopram observed in vitro has been evening with or without food at a antidepressant.●●●
attributed to the demethyl metabolite of starting dose of 10 mg/day. This is an
R-citalopram. In vivo data on the drug effective dose to which most patients References
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annual meeting of the Scandanavian College of
Neuropsychopharmacology; April 2001; Juan
Table 3 Les Pins, France.
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College of Neuropsychopharmacology; April
Escitalopram 0 0 0 0 0 2001; Juan Les Pins, France.
Citalopram + 0 0 + 0 15. Montgomery S, Loft H, Sanchez C, Reines E,
Fluoxetine + ++ +/++ +++ ++ Papp M. Escitalopram (S-enantiomer of citalo-
pram): clinical efficacy and onset of action
Fluvoxamine +++ ++ +++ + ++ predicted from a rat model. Pharmacol Toxicol.
Paroxetine + + + +++ + 2001;88:282-286.
Sertraline + + +/++ + + 16. Mitchell P, Hogg S. Behavioural effects of esci-
talopram predict potent antidepressant activ-
ity [abstract]. Biol Psychiatry. 2001;49(suppl
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Adapted from: Greenblatt D, von Moltke L, Hesse L, Giancarlo G, Harmatz J, Shader R. The S-enan- effects in rodent anxiety models. Paper presented
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[abstract]. Biol Psychiatry. 2001;49(suppl 8):48S. Association; May 30, 2001; Boca Raton, Fla.
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continued on page 41
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